document_title: G protein-coupled receptor

question_text: where is the g protein linked receptor located

question_tokens: where is the g protein linked receptor located

text: G protein-coupled receptor

text: History and significance[edit]

text: The 2012 Nobel Prize in Chemistry was awarded to Brian Kobilka and Robert Lefkowitz for their work that was "crucial for understanding how G protein-coupled receptors function".[10] There have been at least seven other Nobel Prizes awarded for some aspect of G protein–mediated signaling. As of 2012, two of the top ten global best-selling drugs (Advair Diskus and Abilify) act by targeting G protein-coupled receptors.[11]

text: Classification[edit]

text: The exact size of the GPCR superfamily is unknown, but nearly 800 different human genes (or ~ 4% of the entire protein-coding genome) have been predicted to code for them from genome sequence analysis.[12] Although numerous classification schemes have been proposed, the superfamily was classically divided into three main classes (A, B, and C) with no detectable shared sequence homology between classes.

text: The largest class by far is class A, which accounts for nearly 85% of the GPCR genes. Of class A GPCRs, over half of these are predicted to encode olfactory receptors, while the remaining receptors are liganded by known endogenous compounds or are classified as orphan receptors. Despite the lack of sequence homology between classes, all GPCRs have a common structure and mechanism of signal transduction. The very large rhodopsin A group has been further subdivided into 19 subgroups (A1-A19).[13]

text: More recently, an alternative classification system called GRAFS (Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, Secretin) has been proposed.[12] According to the classical A-F system, GPCRs can be grouped into 6 classes based on sequence homology and functional similarity:[14][15][16][17]

text:
Class A (or 1) (Rhodopsin-like)
Class B (or 2) (Secretin receptor family)
Class C (or 3) (Metabotropic glutamate/pheromone)
Class D (or 4) (Fungal mating pheromone receptors)
Class E (or 5) (Cyclic AMP receptors)
Class F (or 6) (Frizzled/Smoothened)

text: An early study based on available DNA sequence suggested that the human genome encodes roughly 750 G protein-coupled receptors,[18] about 350 of which detect hormones, growth factors, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions.

text: Some web-servers[19] and bioinformatics prediction methods[20][21] have been used for predicting the classification of GPCRs according to their amino acid sequence alone, by means of the pseudo amino acid composition approach.

text: Physiological roles[edit]

text: GPCRs are involved in a wide variety of physiological processes. Some examples of their physiological roles include:

text:
The visual sense: The opsins, gradually evolved from early GPCRs over 650 million years ago, use a photoisomerization reaction to translate electromagnetic radiation into cellular signals. Rhodopsin, for example, uses the conversion of 11-cis-retinal to all-trans-retinal for this purpose.
The gustatory sense (taste): GPCRs in taste cells mediate release of gustducin in response to bitter- and sweet-tasting substances.
The sense of smell: Receptors of the olfactory epithelium bind odorants (olfactory receptors) and pheromones (vomeronasal receptors)
Behavioral and mood regulation: Receptors in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, GABA, and glutamate
Regulation of immune system activity and inflammation: Chemokine receptors bind ligands that mediate intercellular communication between cells of the immune system; receptors such as histamine receptors bind inflammatory mediators and engage target cell types in the inflammatory response. GPCRs are also involved in immune-modulation and directly involved in suppression of TLR-induced immune responses from T cells.[22]
Autonomic nervous system transmission: Both the sympathetic and parasympathetic nervous systems are regulated by GPCR pathways, responsible for control of many automatic functions of the body such as blood pressure, heart rate, and digestive processes
Cell density sensing: A novel GPCR role in regulating cell density sensing.
Homeostasis modulation (e.g., water balance).[23]
Involved in growth and metastasis of some types of tumors.[24]
Used in the endocrine system for peptide and amino-acid derivative hormones that bind to GCPRs on the cell membrane of a target cell. This activates cAMP, which in turn activates several kinases, allowing for a cellular response, such as transcription.

text: Receptor structure[edit]

text: GPCRs are integral membrane proteins that possess seven membrane-spanning domains or transmembrane helices.[25][26] The extracellular parts of the receptor can be glycosylated. These extracellular loops also contain two highly conserved cysteine residues that form disulfide bonds to stabilize the receptor structure. Some seven-transmembrane helix proteins (channelrhodopsin) that resemble GPCRs may contain ion channels, within their protein.

text: In 2000, the first crystal structure of a mammalian GPCR, that of bovine rhodopsin (1F88), was solved.[27] In 2007, the first structure of a human GPCR was solved [28][1][29] This human β2-adrenergic receptor GPCR structure proved highly similar to the bovine rhodopsin. The structures of activated or agonist-bound GPCRs have also been determined.[30][31][32][33] These structures indicate how ligand binding at the extracellular side of a receptor leads to conformational changes in the cytoplasmic side of the receptor. The biggest change is an outward movement of the cytoplasmic part of the 5th and 6th transmembrane helix (TM5 and TM6). The structure of activated beta-2 adrenergic receptor in complex with Gs confirmed that the Gα binds to a cavity created by this movement.[34]

text: GPCR are evolutionarily related to some other proteins with 7 transmembrane domains, such as microbial rhodopsins and adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2). However, these 7TMH receptors and channels do not associate with G proteins. In addition, ADIPOR1 and ADIPOR2 are oriented oppositely to GPCRs in the membrane (i.e. GPCRs usually have an extracellular N-terminus, cytoplasmic C-terminus, whereas ADIPORs are inverted).[35]

text: Structure-function relationships[edit]

text: In terms of structure, GPCRs are characterized by an extracellular N-terminus, followed by seven transmembrane (7-TM) α-helices (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally an intracellular C-terminus. The GPCR arranges itself into a tertiary structure resembling a barrel, with the seven transmembrane helices forming a cavity within the plasma membrane that serves a ligand-binding domain that is often covered by EL-2. Ligands may also bind elsewhere, however, as is the case for bulkier ligands (e.g., proteins or large peptides), which instead interact with the extracellular loops, or, as illustrated by the class C metabotropic glutamate receptors (mGluRs), the N-terminal tail. The class C GPCRs are distinguished by their large N-terminal tail, which also contains a ligand-binding domain. Upon glutamate-binding to an mGluR, the N-terminal tail undergoes a conformational change that leads to its interaction with the residues of the extracellular loops and TM domains. The eventual effect of all three types of agonist-induced activation is a change in the relative orientations of the TM helices (likened to a twisting motion) leading to a wider intracellular surface and "revelation" of residues of the intracellular helices and TM domains crucial to signal transduction function (i.e., G-protein coupling). Inverse agonists and antagonists may also bind to a number of different sites, but the eventual effect must be prevention of this TM helix reorientation.[2]

text: The structure of the N- and C-terminal tails of GPCRs may also serve important functions beyond ligand-binding. For example, The C-terminus of M3 muscarinic receptors is sufficient, and the six-amino-acid polybasic (KKKRRK) domain in the C-terminus is necessary for its preassembly with Gq proteins.[36] In particular, the C-terminus often contains serine (Ser) or threonine (Thr) residues that, when phosphorylated, increase the affinity of the intracellular surface for the binding of scaffolding proteins called β-arrestins (β-arr).[37] Once bound, β-arrestins both sterically prevent G-protein coupling and may recruit other proteins, leading to the creation of signaling complexes involved in extracellular-signal regulated kinase (ERK) pathway activation or receptor endocytosis (internalization). As the phosphorylation of these Ser and Thr residues often occurs as a result of GPCR activation, the β-arr-mediated G-protein-decoupling and internalization of GPCRs are important mechanisms of desensitization.[38] In addition, internalized "mega-complexes" consisting of a single GPCR, β-arr(in the tail conformation),[39][40] and heterotrimeric G protein exist and may account for protein signaling from endosomes.[41]

text: A final common structural theme among GPCRs is palmitoylation of one or more sites of the C-terminal tail or the intracellular loops. Palmitoylation is the covalent modification of cysteine (Cys) residues via addition of hydrophobic acyl groups, and has the effect of targeting the receptor to cholesterol- and sphingolipid-rich microdomains of the plasma membrane called lipid rafts. As many of the downstream transducer and effector molecules of GPCRs (including those involved in negative feedback pathways) are also targeted to lipid rafts, this has the effect of facilitating rapid receptor signaling.

text: GPCRs respond to extracellular signals mediated by a huge diversity of agonists, ranging from proteins to biogenic amines to protons, but all transduce this signal via a mechanism of G-protein coupling. This is made possible by a guanine-nucleotide exchange factor (GEF) domain primarily formed by a combination of IL-2 and IL-3 along with adjacent residues of the associated TM helices.

text: Mechanism[edit]

text: The G protein-coupled receptor is activated by an external signal in the form of a ligand or other signal mediator. This creates a conformational change in the receptor, causing activation of a G protein. Further effect depends on the type of G protein. G proteins are subsequently inactivated by GTPase activating proteins, known as RGS proteins.

text: Ligand binding[edit]

text:
GPCRs include one or more receptors for the following ligands:
sensory signal mediators (e.g., light and olfactory stimulatory molecules);
adenosine, bombesin, bradykinin, endothelin, γ-aminobutyric acid (GABA), hepatocyte growth factor (HGF), melanocortins, neuropeptide Y, opioid peptides, opsins, somatostatin, GH, tachykinins, members of the vasoactive intestinal peptide family, and vasopressin;
biogenic amines (e.g., dopamine, epinephrine, norepinephrine, histamine, serotonin, and melatonin);
glutamate (metabotropic effect);
glucagon;
acetylcholine (muscarinic effect);
chemokines;
lipid mediators of inflammation (e.g., prostaglandins, prostanoids, platelet-activating factor, and leukotrienes);
peptide hormones (e.g., calcitonin, C5a anaphylatoxin, follicle-stimulating hormone [FSH], gonadotropin-releasing hormone [GnRH], neurokinin, thyrotropin-releasing hormone [TRH], and oxytocin);
and endocannabinoids.

text: GPCRs that act as receptors for stimuli that have not yet been identified are known as orphan receptors.

text: However, in other types of receptors that have been studied, wherein ligands bind externally to the membrane, the ligands of GPCRs typically bind within the transmembrane domain. However, protease-activated receptors are activated by cleavage of part of their extracellular domain.[43]

text: Conformational change[edit]

text: The transduction of the signal through the membrane by the receptor is not completely understood. It is known that in the inactive state, the GPCR is bound to a heterotrimeric G protein complex. Binding of an agonist to the GPCR results in a conformational change in the receptor that is transmitted to the bound Gα subunit of the heterotrimeric G protein via protein domain dynamics. The activated Gα subunit exchanges GTP in place of GDP which in turn triggers the dissociation of Gα subunit from the Gβγ dimer and from the receptor. The dissociated Gα and Gβγ subunits interact with other intracellular proteins to continue the signal transduction cascade while the freed GPCR is able to rebind to another heterotrimeric G protein to form a new complex that is ready to initiate another round of signal transduction.[44]

text: It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive biophysical states.[45] The binding of ligands to the receptor may shift the equilibrium toward the active receptor states. Three types of ligands exist: Agonists are ligands that shift the equilibrium in favour of active states; inverse agonists are ligands that shift the equilibrium in favour of inactive states; and neutral antagonists are ligands that do not affect the equilibrium. It is not yet known how exactly the active and inactive states differ from each other.

text: G-protein activation/deactivation cycle[edit]

text: When the receptor is inactive, the GEF domain may be bound to an also inactive α-subunit of a heterotrimeric G-protein. These "G-proteins" are a trimer of α, β, and γ subunits (known as Gα, Gβ, and Gγ, respectively) that is rendered inactive when reversibly bound to Guanosine diphosphate (GDP) (or, alternatively, no guanine nucleotide) but active when bound to guanosine triphosphate (GTP). Upon receptor activation, the GEF domain, in turn, allosterically activates the G-protein by facilitating the exchange of a molecule of GDP for GTP at the G-protein's α-subunit. The cell maintains a 10:1 ratio of cytosolic GTP:GDP so exchange for GTP is ensured. At this point, the subunits of the G-protein dissociate from the receptor, as well as each other, to yield a Gα-GTP monomer and a tightly interacting Gβγ dimer, which are now free to modulate the activity of other intracellular proteins. The extent to which they may diffuse, however, is limited due to the palmitoylation of Gα and the presence of an isoprenoid moiety that has been covalently added to the C-termini of Gγ.

text: Because Gα also has slow GTP→GDP hydrolysis capability, the inactive form of the α-subunit (Gα-GDP) is eventually regenerated, thus allowing reassociation with a Gβγ dimer to form the "resting" G-protein, which can again bind to a GPCR and await activation. The rate of GTP hydrolysis is often accelerated due to the actions of another family of allosteric modulating proteins called Regulators of G-protein Signaling, or RGS proteins, which are a type of GTPase-Activating Protein, or GAP. In fact, many of the primary effector proteins (e.g., adenylate cyclases) that become activated/inactivated upon interaction with Gα-GTP also have GAP activity. Thus, even at this early stage in the process, GPCR-initiated signaling has the capacity for self-termination.

text: Crosstalk[edit]

text: GPCRs downstream signals have been shown to possibly interact with integrin signals, such as FAK.[46] Integrin signaling will phosphorylate FAK, which can then decrease GPCR Gαs activity.

text: Signaling[edit]

text: If a receptor in an active state encounters a G protein, it may activate it. Some evidence suggests that receptors and G proteins are actually pre-coupled.[36] For example, binding of G proteins to receptors affects the receptor's affinity for ligands. Activated G proteins are bound to GTP.

text: Further signal transduction depends on the type of G protein. The enzyme adenylate cyclase is an example of a cellular protein that can be regulated by a G protein, in this case the G protein Gs. Adenylate cyclase activity is activated when it binds to a subunit of the activated G protein. Activation of adenylate cyclase ends when the G protein returns to the GDP-bound state.

text: Adenylate cyclases (of which 9 membrane-bound and one cytosolic forms are known in humans) may also be activated or inhibited in other ways (e.g., Ca2+/Calmodulin binding), which can modify the activity of these enzymes in an additive or synergistic fashion along with the G proteins.

text: The signaling pathways activated through a GPCR are limited by the primary sequence and tertiary structure of the GPCR itself but ultimately determined by the particular conformation stabilized by a particular ligand, as well as the availability of transducer molecules. Currently, GPCRs are considered to utilize two primary types of transducers: G-proteins and β-arrestins. Because β-arr's have high affinity only to the phosphorylated form of most GPCRs (see above or below), the majority of signaling is ultimately dependent upon G-protein activation. However, the possibility for interaction does allow for G-protein-independent signaling to occur.

text: G-protein-dependent signaling[edit]

text: There are three main G-protein-mediated signaling pathways, mediated by four sub-classes of G-proteins distinguished from each other by sequence homology (Gαs, Gαi/o, Gαq/11, and Gα12/13). Each sub-class of G-protein consists of multiple proteins, each the product of multiple genes or splice variations that may imbue them with differences ranging from subtle to distinct with regard to signaling properties, but in general they appear reasonably grouped into four classes. Because the signal transducing properties of the various possible βγ combinations do not appear to radically differ from one another, these classes are defined according to the isoform of their α-subunit.[8]:1163

text: While most GPCRs are capable of activating more than one Gα-subtype, they also show a preference for one subtype over another. When the subtype activated depends on the ligand that is bound to the GPCR, this is called functional selectivity (also known as agonist-directed trafficking, or conformation-specific agonism). However, the binding of any single particular agonist may also initiate activation of multiple different G-proteins, as it may be capable of stabilizing more than one conformation of the GPCR's GEF domain, even over the course of a single interaction. In addition, a conformation that preferably activates one isoform of Gα may activate another if the preferred is less available. Furthermore, feedback pathways may result in receptor modifications (e.g., phosphorylation) that alter the G-protein preference. Regardless of these various nuances, the GPCR's preferred coupling partner is usually defined according to the G-protein most obviously activated by the endogenous ligand under most physiological or experimental conditions.

text: Gα signaling[edit]

text:
The effector of both the Gαs and Gαi/o pathways is the cyclic-adenosine monophosphate (cAMP)-generating enzyme adenylate cyclase, or AC. While there are ten different AC gene products in mammals, each with subtle differences in tissue distribution or function, all catalyze the conversion of cytosolic adenosine triphosphate (ATP) to cAMP, and all are directly stimulated by G-proteins of the Gαs class. In contrast, however, interaction with Gα subunits of the Gαi/o type inhibits AC from generating cAMP. Thus, a GPCR coupled to Gαs counteracts the actions of a GPCR coupled to Gαi/o, and vice versa. The level of cytosolic cAMP may then determine the activity of various ion channels as well as members of the ser/thr-specific protein kinase A (PKA) family. Thus cAMP is considered a second messenger and PKA a secondary effector.
The effector of the Gαq/11 pathway is phospholipase C-β (PLCβ), which catalyzes the cleavage of membrane-bound phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers inositol (1,4,5) trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on IP3 receptors found in the membrane of the endoplasmic reticulum (ER) to elicit Ca2+ release from the ER, while DAG diffuses along the plasma membrane where it may activate any membrane localized forms of a second ser/thr kinase called protein kinase C (PKC). Since many isoforms of PKC are also activated by increases in intracellular Ca2+, both these pathways can also converge on each other to signal through the same secondary effector. Elevated intracellular Ca2+ also binds and allosterically activates proteins called calmodulins, which in turn go on to bind and allosterically activate enzymes such as Ca2+/calmodulin-dependent kinases (CAMKs).
The effectors of the Gα12/13 pathway are three RhoGEFs (p115-RhoGEF, PDZ-RhoGEF, and LARG), which, when bound to Gα12/13 allosterically activate the cytosolic small GTPase, Rho. Once bound to GTP, Rho can then go on to activate various proteins responsible for cytoskeleton regulation such as Rho-kinase (ROCK). Most GPCRs that couple to Gα12/13 also couple to other sub-classes, often Gαq/11.

text: Gβγ signaling[edit]

text: The above descriptions ignore the effects of Gβγ–signalling, which can also be important, in particular in the case of activated Gαi/o-coupled GPCRs. The primary effectors of Gβγ are various ion channels, such as G-protein-regulated inwardly rectifying K+ channels (GIRKs), P/Q- and N-type voltage-gated Ca2+ channels, as well as some isoforms of AC and PLC, along with some phosphoinositide-3-kinase (PI3K) isoforms.

text: G-protein-independent signaling[edit]

text: Although they are classically thought of working only together, GPCRs may signal through G-protein-independent mechanisms, and heterotrimeric G-proteins may play functional roles independent of GPCRs. GPCRs may signal independently through many proteins already mentioned for their roles in G-protein-dependent signaling such as β-arrs, GRKs, and Srcs. In addition, further scaffolding proteins involved in subcellular localization of GPCRs (e.g., PDZ-domain-containing proteins) may also act as signal transducers. Most often the effector is a member of the MAPK family.

text: Examples[edit]

text: In the late 1990s, evidence began accumulating to suggest that some GPCRs are able to signal without G proteins. The ERK2 mitogen-activated protein kinase, a key signal transduction mediator downstream of receptor activation in many pathways, has been shown to be activated in response to cAMP-mediated receptor activation in the slime mold D. discoideum despite the absence of the associated G protein α- and β-subunits.[47]

text: In mammalian cells, the much-studied β2-adrenoceptor has been demonstrated to activate the ERK2 pathway after arrestin-mediated uncoupling of G-protein-mediated signaling. Therefore, it seems likely that some mechanisms previously believed related purely to receptor desensitisation are actually examples of receptors switching their signaling pathway, rather than simply being switched off.

text: In kidney cells, the bradykinin receptor B2 has been shown to interact directly with a protein tyrosine phosphatase. The presence of a tyrosine-phosphorylated ITIM (immunoreceptor tyrosine-based inhibitory motif) sequence in the B2 receptor is necessary to mediate this interaction and subsequently the antiproliferative effect of bradykinin.[48]

text: GPCR-independent signaling by heterotrimeric G-proteins[edit]

text: Although it is a relatively immature area of research, it appears that heterotrimeric G-proteins may also take part in non-GPCR signaling. There is evidence for roles as signal transducers in nearly all other types of receptor-mediated signaling, including integrins, receptor tyrosine kinases (RTKs), cytokine receptors (JAK/STATs), as well as modulation of various other "accessory" proteins such as GEFs, guanine-nucleotide dissociation inhibitors (GDIs) and protein phosphatases. There may even be specific proteins of these classes whose primary function is as part of GPCR-independent pathways, termed activators of G-protein signalling (AGS). Both the ubiquity of these interactions and the importance of Gα vs. Gβγ subunits to these processes are still unclear.

text: Details of cAMP and PIP2 pathways[edit]

text: There are two principal signal transduction pathways involving the G protein-linked receptors: the cAMP signal pathway and the phosphatidylinositol signal pathway.[7]

text: cAMP signal pathway[edit]

text: The cAMP signal transduction contains 5 main characters: stimulative hormone receptor (Rs) or inhibitory hormone receptor (Ri); stimulative regulative G-protein (Gs) or inhibitory regulative G-protein (Gi); adenylyl cyclase; protein kinase A (PKA); and cAMP phosphodiesterase.

text: Stimulative hormone receptor (Rs) is a receptor that can bind with stimulative signal molecules, while inhibitory hormone receptor (Ri) is a receptor that can bind with inhibitory signal molecules.

text: Stimulative regulative G-protein is a G-protein linked to stimulative hormone receptor (Rs), and its α subunit upon activation could stimulate the activity of an enzyme or other intracellular metabolism. On the contrary, inhibitory regulative G-protein is linked to an inhibitory hormone receptor, and its α subunit upon activation could inhibit the activity of an enzyme or other intracellular metabolism.

text: Adenylyl cyclase is a 12-transmembrane glycoprotein that catalyzes ATP to form cAMP with the help of cofactor Mg2+ or Mn2+. The cAMP produced is a second messenger in cellular metabolism and is an allosteric activator of protein kinase A.

text: Protein kinase A is an important enzyme in cell metabolism due to its ability to regulate cell metabolism by phosphorylating specific committed enzymes in the metabolic pathway. It can also regulate specific gene expression, cellular secretion, and membrane permeability. The protein enzyme contains two catalytic subunits and two regulatory subunits. When there is no cAMP，the complex is inactive. When cAMP binds to the regulatory subunits, their conformation is altered, causing the dissociation of the regulatory subunits, which activates protein kinase A and allows further biological effects.

text: These signals then can be terminated by cAMP phosphodiesterase, which is an enzyme that degrades cAMP to 5'-AMP and inactivates protein kinase A.

text: Phosphatidylinositol signal pathway[edit]

text: In the phosphatidylinositol signal pathway, the extracellular signal molecule binds with the G-protein receptor (Gq) on the cell surface and activates phospholipase C, which is located on the plasma membrane. The lipase hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds with the IP3 receptor in the membrane of the smooth endoplasmic reticulum and mitochondria to open Ca2+ channels. DAG helps activate protein kinase C (PKC), which phosphorylates many other proteins, changing their catalytic activities, leading to cellular responses.

text: The effects of Ca2+ are also remarkable: it cooperates with DAG in activating PKC and can activate the CaM kinase pathway, in which calcium-modulated protein calmodulin (CaM) binds Ca2+, undergoes a change in conformation, and activates CaM kinase II, which has unique ability to increase its binding affinity to CaM by autophosphorylation, making CaM unavailable for the activation of other enzymes. The kinase then phosphorylates target enzymes, regulating their activities. The two signal pathways are connected together by Ca2+-CaM, which is also a regulatory subunit of adenylyl cyclase and phosphodiesterase in the cAMP signal pathway.

text: Receptor regulation[edit]

text: GPCRs become desensitized when exposed to their ligand for a long period of time. There are two recognized forms of desensitization: 1) homologous desensitization, in which the activated GPCR is downregulated; and 2) heterologous desensitization, wherein the activated GPCR causes downregulation of a different GPCR. The key reaction of this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor domain by protein kinases.

text: Phosphorylation by cAMP-dependent protein kinases[edit]

text: Cyclic AMP-dependent protein kinases (protein kinase A) are activated by the signal chain coming from the G protein (that was activated by the receptor) via adenylate cyclase and cyclic AMP (cAMP). In a feedback mechanism, these activated kinases phosphorylate the receptor. The longer the receptor remains active the more kinases are activated and the more receptors are phosphorylated. In β2-adrenoceptors, this phosphorylation results in the switching of the coupling from the Gs class of G-protein to the Gi class.[49] cAMP-dependent PKA mediated phosphorylation can cause heterologous desensitisation in receptors other than those activated.[50]

text: Phosphorylation by GRKs[edit]

text: The G protein-coupled receptor kinases (GRKs) are protein kinases that phosphorylate only active GPCRs.[51] G-protein-coupled receptor kinases (GRKs) are key modulators of G-protein-coupled receptor (GPCR) signaling. They constitute a family of seven mammalian serine-threonine protein kinases that phosphorylate agonist-bound receptor. GRKs-mediated receptor phosphorylation rapidly initiates profound impairment of receptor signaling and desensitization. Activity of GRKs and subcellular targeting is tightly regulated by interaction with receptor domains, G protein subunits, lipids, anchoring proteins and calcium-sensitive proteins.[52]

text: Phosphorylation of the receptor can have two consequences:

text:
Translocation: The receptor is, along with the part of the membrane it is embedded in, brought to the inside of the cell, where it is dephosphorylated within the acidic vesicular environment[53] and then brought back. This mechanism is used to regulate long-term exposure, for example, to a hormone, by allowing resensitisation to follow desensitisation. Alternatively, the receptor may undergo lysozomal degradation, or remain internalised, where it is thought to participate in the initiation of signalling events, the nature of which depending on the internalised vesicle's subcellular localisation.[50]
Arrestin linking: The phosphorylated receptor can be linked to arrestin molecules that prevent it from binding (and activating) G proteins, in effect switching it off for a short period of time. This mechanism is used, for example, with rhodopsin in retina cells to compensate for exposure to bright light. In many cases, arrestin's binding to the receptor is a prerequisite for translocation. For example, beta-arrestin bound to β2-adrenoreceptors acts as an adaptor for binding with clathrin, and with the beta-subunit of AP2 (clathrin adaptor molecules); thus, the arrestin here acts as a scaffold assembling the components needed for clathrin-mediated endocytosis of β2-adrenoreceptors.[54][55]

text: Mechanisms of GPCR signal termination[edit]

text: As mentioned above, G-proteins may terminate their own activation due to their intrinsic GTP→GDP hydrolysis capability. However, this reaction proceeds at a slow rate (≈.02 times/sec) and, thus, it would take around 50 seconds for any single G-protein to deactivate if other factors did not come into play. Indeed, there are around 30 isoforms of RGS proteins that, when bound to Gα through their GAP domain, accelerate the hydrolysis rate to ≈30 times/sec. This 1500-fold increase in rate allows for the cell to respond to external signals with high speed, as well as spatial resolution due to limited amount of second messenger that can be generated and limited distance a G-protein can diffuse in 0.03 seconds. For the most part, the RGS proteins are promiscuous in their ability to activate G-proteins, while which RGS is involved in a given signaling pathway seems more determined by the tissue and GPCR involved than anything else. In addition, RGS proteins have the additional function of increasing the rate of GTP-GDP exchange at GPCRs, (i.e., as a sort of co-GEF) further contributing to the time resolution of GPCR signaling.

text: In addition, the GPCR may be desensitized itself. This can occur as:

text:
a direct result of ligand occupation, wherein the change in conformation allows recruitment of GPCR-Regulating Kinases (GRKs), which go on to phosphorylate various serine/threonine residues of IL-3 and the C-terminal tail. Upon GRK phosphorylation, the GPCR's affinity for β-arrestin (β-arrestin-1/2 in most tissues) is increased, at which point β-arrestin may bind and act to both sterically hinder G-protein coupling as well as initiate the process of receptor internalization through clathrin-mediated endocytosis. Because only the liganded receptor is desensitized by this mechanism, it is called homologous desensitization
the affinity for β-arrestin may be increased in a ligand occupation and GRK-independent manner through phosphorylation of different ser/thr sites (but also of IL-3 and the C-terminal tail) by PKC and PKA. These phosphorylations are often sufficient to impair G-protein coupling on their own as well.[citation needed]
PKC/PKA may, instead, phosphorylate GRKs, which can also lead to GPCR phosphorylation and β-arrestin binding in an occupation-independent manner. These latter two mechanisms allow for desensitization of one GPCR due to the activities of others, or heterologous desensitization. GRKs may also have GAP domains and so may contribute to inactivation through non-kinase mechanisms as well. A combination of these mechanisms may also occur.

text: Once β-arrestin is bound to a GPCR, it undergoes a conformational change allowing it to serve as a scaffolding protein for an adaptor complex termed AP-2, which in turn recruits another protein called clathrin. If enough receptors in the local area recruit clathrin in this manner, they aggregate and the membrane buds inwardly as a result of interactions between the molecules of clathrin, in a process called opsonization. Once the pit has been pinched off the plasma membrane due to the actions of two other proteins called amphiphysin and dynamin, it is now an endocytic vesicle. At this point, the adapter molecules and clathrin have dissociated, and the receptor is either trafficked back to the plasma membrane or targeted to lysosomes for degradation.

text: At any point in this process, the β-arrestins may also recruit other proteins—such as the non-receptor tyrosine kinase (nRTK), c-SRC—which may activate ERK1/2, or other mitogen-activated protein kinase (MAPK) signaling through, for example, phosphorylation of the small GTPase, Ras, or recruit the proteins of the ERK cascade directly (i.e., Raf-1, MEK, ERK-1/2) at which point signaling is initiated due to their close proximity to one another. Another target of c-SRC are the dynamin molecules involved in endocytosis. Dynamins polymerize around the neck of an incoming vesicle, and their phosphorylation by c-SRC provides the energy necessary for the conformational change allowing the final "pinching off" from the membrane.

text: GPCR cellular regulation[edit]

text:
Receptor desensitization is mediated through a combination phosphorylation, β-arr binding, and endocytosis as described above. Downregulation occurs when endocytosed receptor is embedded in an endosome that is trafficked to merge with an organelle called a lysosome. Because lysosomal membranes are rich in proton pumps, their interiors have low pH (≈4.8 vs. the pH≈7.2 cytosol), which acts to denature the GPCRs. In addition, lysosomes contain many degradative enzymes, including proteases, which can function only at such low pH, and so the peptide bonds joining the residues of the GPCR together may be cleaved. Whether or not a given receptor is trafficked to a lysosome, detained in endosomes, or trafficked back to the plasma membrane depends on a variety of factors, including receptor type and magnitude of the signal.
GPCR regulation is additionally mediated by gene transcription factors. These factors can increase or decrease gene transcription and thus increase or decrease the generation of new receptors (up- or down-regulation) that travel to the cell membrane.

text: Receptor oligomerization[edit]

text: G-protein-coupled receptor oligomerisation is a widespread phenomenon. One of the best-studied examples is the metabotropic GABAB receptor. This so-called constitutive receptor is formed by heterodimerization of GABABR1 and GABABR2 subunits. Expression of the GABABR1 without the GABABR2 in heterologous systems leads to retention of the subunit in the endoplasmic reticulum. Expression of the GABABR2 subunit alone, meanwhile, leads to surface expression of the subunit, although with no functional activity (i.e., the receptor does not bind agonist and cannot initiate a response following exposure to agonist). Expression of the two subunits together leads to plasma membrane expression of functional receptor. It has been shown that GABABR2 binding to GABABR1 causes masking of a retention signal[56] of functional receptors.[57]

text: Origin and diversification of the superfamily[edit]

text: Signal transduction mediated by the superfamily of GPCRs dates back to the origin of multicellularity. Mammalian-like GPCRs are found in fungi, and have been classified according to the GRAFS classification system based on GPCR fingerprints.[58] Identification of the superfamily members across the eukaryotic domain, and comparison of the family-specific motifs, have shown that the superfamily of GPCRs have a common origin.[59] Characteristic motifs indicate that three of the five GRAFS families, Rhodopsin, Adhesion, and Frizzled, evolved from the Dictyostelium discoideum cAMP receptors before the split of Opisthokonts. Later, the Secretin family evolved from the Adhesion GPCR receptor family before the split of nematodes.


document_title: List of governors-general of India

question_text: last governor general of india under east india company

root

text: List of governors-general of India

text: The Regulating Act of 1773 created the office with the title of Governor-General of the Presidency of Fort William, or Governor-General of Bengal to be appointed by the Court of Directors of the East India Company (EIC). The Court of Directors assigned a Council of Four (based in India) to assist the Governor General, and decision of council was binding on the Governor General during 1773-1784.

tag: p

text: The Saint Helena Act 1833 (or Government of India Act 1833) re-designated the office with the title of Governor-General of India.

text: After the Indian Rebellion of 1857, the company rule was brought to an end, and the British India along with princely states came under the direct rule of the British Crown. The Government of India Act 1858 created the office of Secretary of State for India in 1858 to oversee the affairs of India, which was advised by a new Council of India with 15 members (based in London). The existing Council of Four was formally renamed as the Council of Governor General of India or Executive Council of India. The Council of India was later abolished by Government of India Act 1935.

text: Following the adoption of the Government of India Act of 1858, the Governor-General as representing the Crown became known as the Viceroy. The designation 'Viceroy', although it was most frequently used in ordinary parlance, had no statutory authority, and was never employed by Parliament. Although the Proclamation of 1858 announcing the assumption of the government of India by the Crown referred to Lord Canning as "first Viceroy and Governor-General", none of the Warrants appointing his successors referred to them as 'Viceroys', and the title, which was frequently used in Warrants dealing with precedence and in public notifications, was basically one of ceremony used in connection with the state and social functions of the Sovereign's representative. The Governor-General continued to be the sole representative of the Crown, and the Government of India continued to be vested in the Governor-General-in-Council.[1]

text: From the year 1858 onwards, the appointments of Governor-General of India were made by the British Crown upon the advice of Secretary of State for India. The office of Governor-General continued to exist as a ceremonial post in each of the new dominions until they adopted republican constitutions in 1950 and 1956 Respectively.

text: List of Governor-Generals[edit]

text:
Portrait

Name(Birth–Death)

Term of office

Notable events

Appointer

Governors Generals of the Presidency of Fort William (Bengal), 1773–1833

Warren Hastings (1732-1818)

20 October1773[nb 1]

1 February1785

Regulating Act of 1773
Supreme Council Of Bengal
Asiatic Society of Bengal
Stopped Mughal pension to Shah Alam II
Stopped Diarchy in Bengal
New Sanskrit School by Jonathan Deccan
Moved Treasury from Murshidabad to Calcutta
Bengal Gazette- First Indian newspaper published
First Anglo-Maratha War (1775–82)
Second Anglo-Mysore war (1780–84)
First Rohilla W of 1773–1774
"Ring fence policy"
Second Rohilla War 1779
Experimentation on land settlements. (1772-five years settlement, changed to 1 year in 1776)
English Translation of Bhagwat Gita[2]

East IndiaCompany(1773–1858)

John Macpherson (acting) (1745–1821)

1 February1785

12 September1786

Charles CornwallisThe Marquess Cornwallis [nb 2](1738–1805)

12 September1786

28 October1793

Established lower courts and appellate courts
Permanent Settlement in Bihar and Bengal in 1793
3rd Mysore war
Introduction of Cornwallis Code
Introduction of Civil Services in India

John Shore(1751–1834)

28 October1793

18 March1798

Policy of Non-intervention
Charter Act of 1793
Battle of Kharda between Nizam and Marathas (1795)

Alured Clarke (acting) (1744–1832)

18 March1798

18 May1798

Richard Wellesley, Earl of Mornington [nb 3](1760–1842)

18 May1798

30 July1805

Introduction of Subsidiary Alliance
Fourth Anglo Mysore War 1799
Second Anglo-Maratha War (1803–05)
Fort William College at Calcutta
Formation of Madras Presidency in 1801

The Marquess Cornwallis(1738–1805)

30 July1805

5 October1805

Sir George Barlow, Bt (acting) (1762–1847)

10 October1805

31 July1807

Sepoy mutiny at Vellore

The Lord Minto(1751–1814)

31 July1807

4 October1813

Charter Act of 1813
Treaty of Amritsar, 1809 with Ranjit Singh

Francis Rawdon-Hastings, The Earl of Moira [nb 4](1754–1826)

4 October1813

9 January1823

Ended the policy of Non-intervention
Third Anglo-Maratha War (1816-1818)
Treaty of Sugauli
Creation of Bombay Presidency in 1818
Establishment of Ryotwari System in Madras and
Mahalwari System in Central India,Punjab And Western UP.

John Adam (acting)(1779–1825)

9 January1823

1 August1823

Licensing Regulations

The Lord Amherst[nb 5](1773–1857)

1 August1823

13 March1828

First Anglo-Burmese War (1824–26)
Treaty of Yandabo, 1826

William Butterworth Bayley  (acting) (1782–1860)

13 March1828

4 July1828

Governors-General of India, 1833–1858

Lord William Bentinck(1774–1839)

4 July1828

20 March1835

First Governor General of India
Bengal Sati Regulation, 1829
Charter Act, 1833
Saint Helena Act 1833
English Education Act 1835
Medical College and Hospital, Kolkata

East IndiaCompany(1773–1858)

Charles Metcalfe, Bt (acting) (1785–1846)

20 March1835

4 March1836

Repealed 1823 Licensing Regulations
Known as Liberator of India Press

The Lord Auckland[nb 6](1784–1849)

4 March1836

28 February1842

The Lord Ellenborough(1790–1871)

28 February1842

June1844

William Wilberforce Bird (acting) (1784–1857)

June1844

23 July1844

Henry Hardinge[nb 7](1785–1856)

23 July1844

12 January1848

The First Anglo-Sikh War (1845–46)
The Second Anglo-Sikh War (1848–49)
Treaty of Lahore

The Earl of Dalhousie[nb 8](1812–1860)

12 January1848

28 February1856

Doctrine of Lapse
Charles Wood Despatch
Second Anglo-Burmese War (1852)
First Railway line connecting Bombay and Thane
First telegraph Line was laid between Diamond Harbour to Calcutta.
Post Office Act, 1854
Hindu widow remarriage act 1856
Established Public Works Department
The Second Anglo-Sikh War (1848-1849)
Engineering College was established at Roorkee.[3]

Governors-General and Viceroys of India, 1858–1947

The Viscount Canning[nb 9](1812–1862)

28 February1856

21 March1862

University of Bombay, Calcutta and Madras were set up in 1858
The revolt of 1857
The Government of India Act, 1858
Hindu Widows' Remarriage Act, 1856
System of Budget introduced

Victoria(1837–1901)

The Earl of Elgin(1811–1863)

21 March1862

20 November1863

Robert Napier (acting) (1810–1890)

21 November1863

2 December1863

William Denison (acting) (1804–1871)

2 December1863

12 January1864

Sir John Lawrence, Bt(1811–1879)

12 January1864

12 January1869

Bhutan War
Establishment of Shimla as India's summer capital in 1863

The Earl of Mayo(1822–1872)

12 January1869

8 February1872

Assassinated by a Pathan Sher Ali Afridi
Started the Census.
Opening of Rajkot college in Kathiawar and Mayo College at Ajmer   for political training of Indian Princes
Started Financial Decentralisation

Sir John Strachey (acting) (1823–1907)

9 February1872

23 February1872

The Lord Napier (acting) (1819–1898)

24 February1872

3 May1872

The Lord Northbrook(1826–1904)

3 May1872

12 April1876

The Lord Lytton(1831–1891)

12 April1876

8 June1880

Vernacular Press Act, 1878
Second Anglo-Afghan War
The Indians Arms Act (1878)[4]
1st Delhi Durbar out of 3
Queen Victoria assuming the title of 'Kaiser-i-Hind'

The Marquess of Ripon(1827–1909)

8 June1880

13 December1884

First Factory Act (1881)
Repeal of the Vernacular Press Act (1882)
Ilbert Bill
Government resolution on local self-government (1882)
Appointment of Education Commission under Sir William Hunter

The Earl of Dufferin(1826–1902)

13 December1884

10 December1888

Formation of Indian National Congress
Third Anglo-Burmese War

The Marquess of Lansdowne(1845–1927)

10 December1888

11 October1894

Indian Council Act 1892
Factory Act 1891
Setting up of  Durand Commission (India-Afghanistan)

The Earl of Elgin(1849–1917)

11 October1894

6 January1899

The Lord Curzon of Kedleston[nb 10](1859–1925)

6 January1899

18 November1905

Partition of Bengal (1905)
2st Delhi Durbar out of 3 (1903)
Appointment of Police Commission under Sir Andrew Frazer
Appointment of Raleigh University Commission (1902)
Passing of Indian Universities Act 1904

The Earl of Minto(1845–1914)

18 November1905

23 November1910

Morley-Minto Reforms 1909 or The Indian Councils Act 1909
Split in Congress in 1907
Establishment of Muslim League by Aga Khan (1906)

Edward VII(1901–1910)

The Lord Hardinge of Penshurst(1858–1944)

23 November1910

4 April1916

Third Delhi Durbar (1911)
Transfer of capital from Calcutta to Delhi (1911)
Ghadar Mutiny (1915)

George V(1910–1936)

The Lord Chelmsford(1868–1933)

4 April1916

2 April1921

Formation of Indian Home Rule Movement (1916)
Lucknow Pact (1916)
Montagu-Chelmsford Reforms (1919)
Government of India Act 1919
Rowlatt Act (1919)
Jallianwalla Bagh Massacre (1919)

The Earl of Reading(1860–1935)

2 April1921

3 April1926

Malabar rebellion (1921)
Non-cooperation movement (1921-22)
Chauri Chaura incident (1922)

The Lord Irwin(1881–1959)

3 April1926

18 April1931

Simon Commission (1928)
Nehru Report (1928)
Death of Lala Lajpat Rai (1928)
Fourteen Points of Jinnah (1929)
Purna Swaraj declaration (1930)
Salt March (1930)
Dharasana Satyagraha (1930)
First and Second Round Table Conferences (1930-31)
Allahabad Address (1930)
Gandhi–Irwin Pact (1931)
Execution of Bhagat Singh, Shivaram Rajguru, and Sukhdev Thapar (1931)

The Earl of Willingdon(1866–1941)

18 April1931

18 April1936

Pakistan Declaration (1933)
Government of India Act 1935

The Marquess of Linlithgow(1887–1952)

18 April1936

1 October1943

Indian provincial elections (1937)
Indian entry into World War II (1939)
Day of Deliverance (1939)
Lahore Resolution (1940)
Cripps Mission (1942)
Formation of Indian Legion (1942)
Quit India movement (1942)
Formation of Indian National Army (1942)
Bengal famine (1943)

Edward VIII(1936)

The Viscount Wavell(1883–1950)

1 October1943

21 February1947

C. R. formula (1944)
Simla Conference (1945)
Cabinet Mission (1946)
Direct Action Day (1946)

George VI(1936–1952)

The Viscount Mountbatten of Burma(1900–1979)

21 February1947

15 August1947

Governors-General of the Dominion of India, 1947–1950

The Viscount Mountbatten of Burma[nb 11](1900–1979)

15 August1947

21 June1948

George VI(1936–1952)

C. Rajagopalachari (1878–1972)

21 June1948

26 January1950

tag: table

text:
Jump up ^ Originally joined on 28 April 1772

Jump up ^ Earl Cornwallis from 1762; created Marquess Cornwallis in 1792.

Jump up ^ Created Marquess Wellesley in 1799.

Jump up ^ Created Marquess of Hastings in 1816

Jump up ^ Created Earl Amherst in 1826.

Jump up ^ Created Earl of Auckland in 1839.

Jump up ^ Created Viscount Hardinge in 1846.

Jump up ^ Created Marquess of Dalhousie in 1849.

Jump up ^ Created Earl Canning in 1859.

Jump up ^ The Lord Ampthill was acting Governor-General in 1904

Jump up ^ Created Earl Mountbatten of Burma on 28 October 1947.

tag: ol


document_title: You're a Mean One, Mr. Grinch

question_text: who wrote the lyrics to the grinch song

question_tokens: who wrote the lyrics to the grinch song

text: You're a Mean One, Mr. Grinch

text: History[edit]

text: The lyrics were written by Theodor "Dr. Seuss" Geisel, the music was composed by Albert Hague, and the song was performed by Thurl Ravenscroft. The song's lyrics describe the Grinch as being foul, bad-mannered and sinister, using increasingly creative put-downs, metaphors and similes, beginning with the opening line "you're a mean one, Mr. Grinch".

text: Because Ravenscroft was not credited in the closing credits of the special, it is often mistakenly attributed to Boris Karloff, who served as narrator and the voice of the Grinch in the special but who himself could not sing. Until Ravenscroft was publicly credited, Tennessee Ernie Ford was also speculated to be the voice behind the song.[2]

text: Mainstream and pop acts have covered the song, usually for holiday-themed albums.

text: In 1992, an emerging alternative band from New Jersey named Whirling Dervishes covered the song for their Wish it Would Snow EP. Their cover version took on a cult status in the region and went on to outlast the band's existence eventually becoming one of their only breakthrough hits. The song is still requested regionally during the holidays.[3]

text: American singer and drag queen RuPaul covered the song for his 1997 Christmas album Ho Ho Ho, which incorporated elements from funk.[4] Billboard's Melinda Newman negatively responded to RuPaul's version, writing that "he should have left [it] alone".[5]

text: Jim Carrey sang this song in the 2000 live action film adaptation, Dr. Seuss' How the Grinch Stole Christmas, as the Grinch himself.

text: In 2011, Electric Six performed a cover of the song as part of The AV Club's "Undercover Holiday" series.[6] They went on to perform the song at live shows on their 2011 tour.[7] The band will record the song for inclusion on their upcoming Christmas album A Very Electric SiXmas.[8]

text: In 2013 another New Jersey band, Misfits covered the song for Christmas-themed seven-inch promotion.[9]

text: In 2017, Lindsey Stirling released her version with Sabrina Carpenter singing on her holiday album Warmer in the Winter.[10]


document_title: Prime Minister of Canada

question_text: how long is the term for prime minister of canada

text: Prime Minister of Canada

text: Origin of the office[edit]

text: The position of prime minister is not outlined in any Canadian constitutional document and is mentioned only in passing in the Constitution Act, 1982,[4][5] and the Letters Patent, 1947 issued by King George VI.[6] The office and its functions are instead governed by constitutional conventions and modelled on the same office in the United Kingdom.

text: Qualifications and selection[edit]

text: The prime minister, along with the other ministers in cabinet, is appointed by the governor general on behalf of the monarch.[7] However, by the conventions of responsible government, designed to maintain administrative stability, the governor general will call to form a government the individual most likely to receive the support, or confidence, of a majority of the directly elected members of the House of Commons;[8] as a practical matter, this is often the leader of a party whose members form a majority, or a very large plurality, of Members of Parliament (MPs).[9]

text: While there is no legal requirement for the prime minister to be a member of parliament, for practical and political reasons the prime minister is expected to win a seat very promptly.[10] However, in rare circumstances individuals who are not sitting members of the House of Commons have been appointed to the position of prime minister. Two former prime ministers—Sir John Joseph Caldwell Abbott and Sir Mackenzie Bowell—served in the 1890s while members of the Senate.[11] Both, in their roles as Government Leader in the Senate, succeeded prime ministers who had died in office—John A. Macdonald in 1891 and John Sparrow David Thompson in 1894. That convention has since evolved toward the appointment of an interim leader from the commons in such a scenario.

text: Prime ministers who are not Members of Parliament upon their appointment (or who lose their seats while in office) have since been expected to seek election to the commons as soon as possible. For example, William Lyon Mackenzie King, after losing his seat in the 1925 federal election (that his party won), briefly "governed from the hallway" before winning a by-election a few weeks later. Similarly, John Turner replaced Pierre Trudeau as leader of the Liberal Party in 1984 and subsequently was appointed prime minister while not holding a seat in the House of Commons; Turner won a riding in the next election but the Liberal Party was swept from power. Turner was the last serving prime minister to not hold a commons seat.

text: Should a serving prime minister today lose his or her seat in the legislature, or should a new prime minister be appointed without holding a seat, the typical process that follows is that a junior member in the governing political party will resign to allow the prime minister to run in the resulting by-election.[11] A safe seat is usually chosen; while the Liberal and Conservative parties traditionally observed a convention of not running a candidate against another party's new leader in the by-election, the New Democrats and smaller political parties typically do not follow the same convention. However, if the governing party selects a new leader shortly before an election is due, and that new leader is not a member of the legislature, he or she will normally await the upcoming election before running for a seat in parliament.

text: In a poll conducted by Ipsos-Reid following the first prorogation of the 40th parliament on December 4, 2008, it was found that 51% of the sample group thought the prime minister was directly elected by Canadians.[12][13]

text: Term of office[edit]

text: The Canadian prime minister serves at Her Majesty's pleasure, meaning the post does not have a fixed term. Once appointed and sworn in by the governor general, the prime minister remains in office until he or she resigns, is dismissed, or dies.[14] The lifespan of parliament was limited by the constitution to five years and, though the governor general may still, on the advice of the prime minister, dissolve parliament and issue the writs of election prior to the date mandated by the Canada Elections Act; the King–Byng Affair was the only time since Confederation that the governor general deemed it necessary to refuse his prime minister's request for a general vote. As of 2007, with an amendment to the Elections Act, Section 56.1(2) was changed to limit the term of a majority government to four years, with election day being set as the third Monday in October of the fourth calendar year after the previous polling date.[15]

text: Following parliamentary dissolution, the prime minister must run in the resulting general election if he or she wishes to maintain a seat in the House of Commons. Should the prime minister's party subsequently win a majority of seats in the House of Commons, it is unnecessary to re-appoint the prime minister or again swear him or her into office.[14] If, however, an opposition party wins a majority of seats, the prime minister may resign or be dismissed by the governor general. Should the prime minister's party achieve a minority while an opposition party wins a plurality (i.e., more seats than any other party but less than a majority), the prime minister can attempt to maintain the confidence of the House by forming a coalition with other minority parties. This option was last entertained in 1925.

text: Role and authority[edit]

text: Because the prime minister is, in practice, the most politically powerful member of the Canadian government, he or she is sometimes erroneously referred to as Canada's head of state,[n 2] when, in fact, that post is held by the Canadian monarch, represented by the governor general.[16] The prime minister is, instead, the head of government and is responsible for advising the Crown on how to exercise the Royal Prerogative and its executive powers,[3] which are governed by the constitution and its conventions. However, the function of the prime minister has evolved with increasing power. Today, as per the doctrines of constitutional monarchy, the advice given by the prime minister is ordinarily binding, meaning the prime minister effectively carries out those duties ascribed to the sovereign or governor general, leaving the latter to act in predominantly ceremonial fashions.[17] As such, the prime minister, supported by the Office of the Prime Minister (PMO), controls the appointments of many key figures in Canada's system of governance, including the governor general, the Cabinet, justices of the Supreme Court, senators, heads of crown corporations, ambassadors to foreign countries, the provincial lieutenant governors, and approximately 3,100 other positions. Further, the prime minister plays a prominent role in the legislative process—with the majority of bills put before parliament originating in the Cabinet—and the leadership of the Canadian Armed Forces.

text: Pierre Trudeau is credited with, throughout his tenure as prime minister between 1968 and 1984, consolidating power in the PMO,[18] which is itself filled by political and administrative staff selected at the prime minister's discretion and unaccountable to parliament. At the end of the 20th century and into the 21st, analysts—such as Jeffrey Simpson,[19] Donald Savoie, Andrew Coyne,[20] and John Gomery—argued that both parliament and the Cabinet had become eclipsed by prime ministerial power;[n 3][21] Savoie wrote: "The Canadian prime minister has little in the way of institutional check, at least inside government, to inhibit his ability to have his way."[22] Indeed, the position has been described as undergoing a "presidentialisation",[18][23] to the point that its incumbents publicly outshine the actual head of state (and prime minister's spouses are sometimes called the "First Lady of Canada"[24][25]).[26][27] Former governor general Adrienne Clarkson alluded to what she saw as "an unspoken rivalry" that had developed between the prime minister and the Crown.[28] It has been theorized that such is the case in Canada as its parliament is less influential on the executive than in other countries with Westminster parliamentary systems; particularly, Canada has fewer MPs, a higher turnover rate of MPs after each election, and an Americanised system for selecting political party leaders, leaving them accountable to the party membership rather than caucus, as is the case in the United Kingdom.[29]

text: There do exist checks on the prime minister's power: the commons may revoke its confidence in an incumbent prime minister and Cabinet or caucus revolts can quickly bring down a serving premier and even mere threats of such action can persuade or compel a prime minister to resign his post, as happened with Jean Chrétien. The Reform Act, 2014,[30] codifies the process by which a caucus may trigger a party leadership review and, if necessary, chose an interim leader, thereby making a prime minister more accountable to the MPs in his or her party. Caucuses may choose to follow these rules, though the decision would be made by recorded vote, thereby subjecting the party's choice to public scrutiny.[31]

text: The Senate may delay or impede legislation put forward by the Cabinet, such as when Brian Mulroney's bill creating the Goods and Services Tax (GST) came before the upper chamber and, given Canada's federal nature, the jurisdiction of the federal government is limited to areas prescribed by the constitution. Further, as executive power is constitutionally vested in the monarch, meaning the Royal Prerogative belongs to the Crown and not to any of its ministers,[32][33][34] the sovereign's supremacy over the prime minister in the constitutional order is thus seen as a "rebuff to the pretensions of the elected: As it has been said, when the Prime Minister bows before the Queen, he bows before us [the Canadian people]."[35][36] Either the sovereign or his or her governor general may therefore oppose the prime minister's will in extreme, crisis situations.[n 4] Near the end of her time as governor general, Adrienne Clarkson stated: "My constitutional role has lain in what are called 'reserve powers': making sure that there is a prime minister and a government in place, and exercising the right 'to encourage, to advise, and to warn'[...] Without really revealing any secrets, I can tell you that I have done all three."[37]

text: Privileges[edit]

text: Two official residences are provided to the prime minister—24 Sussex Drive in Ottawa and Harrington Lake, a country retreat in Gatineau Park—as well an office in the Office of the Prime Minister and Privy Council (formerly known as Langevin Block), across from Parliament Hill.[38] For transportation, the prime minister is granted an armoured car and shared use of two official aircraft—a CC-150 Polaris for international flights and a Challenger 601 for domestic trips. The Royal Canadian Mounted Police also furnish constant personal security for the prime minister and his or her family. All of the aforementioned is supplied by the Queen-in-Council through budgets approved by parliament, as is the prime minister's total annual compensation of CAD$347,400.[1] The Prime Minister's total compensation consists of the Member of the House of Commons Basic Sessional Indemnity of CAD$172,400, the Prime Minister Salary of CAD$172,400, and the Prime Minister Car Allowance of CAD$2000.[1]

text: Should a serving or former prime minister die, he or she is accorded a state funeral, wherein their casket lies in state in the Centre Block of Parliament Hill.[39] Only Bowell and the Viscount Bennett were given private funerals, Bennett also being the only former Prime Minister of Canada to die and be buried outside the country and Bowell the only whose funeral was not attended by politicians. John Thompson also died outside Canada, at Windsor Castle, where Queen Victoria permitted his lying-in-state before his body was returned to Canada for a state funeral in Halifax.[40]

text: In earlier years, it was traditional for the monarch to bestow a knighthood on newly appointed Canadian prime ministers. Accordingly, several carried the prefix Sir before their name; of the first eight premiers of Canada, only Alexander Mackenzie refused the honour of a knighthood from Queen Victoria. Following the 1919 Nickle Resolution, however, it was against non-binding policy for the sovereign to grant such honorific titles to Canadians; the last prime minister to be knighted was Sir Robert Borden, who was premier at the time the Nickle Resolution was debated in the House of Commons. Still, Bennett was in 1941, six years after he stepped down as prime minister, elevated to the peerage by King George VI as Viscount Bennett, of Mickleham in the County of Surrey and of Calgary and Hopewell in the Dominion of Canada.[41][42]

text: The Canadian Heraldic Authority (CHA) has granted former prime ministers an augmentation of honour on the personal coat of arms of those who pursued them. The heraldic badge, referred to by the CHA as the mark of the Prime Ministership of Canada,[43] consists of four red maple leaves joined at the stem on a white field ("Argent four maple leaves conjoined in cross at the stem Gules"); the augmentation has, so far, been granted either as a canton sinister or centred in the chief.[43][44][45][46][47] To date, former prime ministers Joe Clark,[43] Pierre Trudeau,[44] John Turner,[45] Brian Mulroney,[46] and Kim Campbell were granted arms with the augmentation.[47]

text: Style of address[edit]

text: Canada continues the Westminster tradition of using the title Prime Minister when one is speaking to the federal head of government directly; this is in contrast to the United States protocol of addressing the federal head of government as mister (as in, Mister President); the Department of Canadian Heritage advises that it is incorrect to use the term Mr Prime Minister.[48] The written form of address for the prime minister should use his or her full parliamentary title: The Right Honourable [name], [post-nominal letters], Prime Minister of Canada. However, while in the House of Commons during Question Period, other members of parliament may address the prime minister as The Right Honourable, Member for [prime minister's riding] or simply The Right Honourable Prime Minister.[49] Former prime ministers retain the prefix The Right Honourable for the remainder of their lives; should they remain sitting MPs, they may be referred as The Right Honourable Member for [member's riding] or by their portfolio title (if appointed to one), as in The Right Honourable Minister of National Defence.

text: In the decades following Confederation, it was common practice to refer to the prime minister as Premier of Canada,[50][51][52] a custom that continued until the First World War, around the time of Robert Borden's premiership.[53][54][55] While contemporary sources will still speak of early prime ministers of Canada as premier,[56][57][58] the modern practice is such that the federal head of government is known almost exclusively as the prime minister, while the provincial heads of government are termed premiers (save for within Quebec and New Brunswick, where the premiers are addressed in French as Premier ministre du [province], literally translated as Prime Minister of [province]).

text: Prime Minister-designate of Canada[edit]

text: The Prime Minister–designate of Canada refers to the person who has been designated as the future prime minister by the Governor General, after either winning a general election, forming a confidence and supply government, or forming an coalition government. The term does not apply to incumbent prime ministers.

text: Activities post-commission[edit]

text: After exiting office, former prime ministers of Canada have engaged in various pursuits. Some remained in politics: Bowell continued to serve as a senator, Stephen Harper returned to the House of Commons as a backbench Member of Parliament, and Bennett moved to the United Kingdom after being elevated to the House of Lords.[59] A number led Her Majesty's Loyal Opposition in the Canadian parliament: John A. Macdonald, Arthur Meighen, Mackenzie King,[60] and Pierre Trudeau, all before being re-appointed as prime minister (Mackenzie King twice); Alexander Mackenzie and John Diefenbaker, both prior to sitting as regular Members of Parliament until their deaths;[61] Wilfrid Laurier dying while still in the post;[62] and Charles Tupper,[63] Louis St. Laurent,[64] and John Turner, each before they returned to private business. Meighen was also appointed to the Senate following his second period as prime minister, but resigned his seat to seek re-election and moved to private enterprise after failing to win a riding.[65] Following Meighen into civilian life were: Robert Borden, who served as Chancellor of Queen's and McGill Universities, as well as working in the financial sector; Lester B. Pearson, who acted as Chancellor of Carleton University;[66] Joe Clark and Kim Campbell, who became university professors, Clark also consultant and Campbell working in international diplomacy and as the director of private companies and chairperson of interest groups; while Pierre Trudeau and Jean Chrétien returned to legal practice.[67] Former prime ministers also commonly penned autobiographies—Tupper,[63] for example—or published their memoirs—such as Diefenbaker and Paul Martin.[61]