The general function of the G alpha (s) subunit (Gs) is to activate adenylate cyclase (Tesmer et al. 1997), which in turn produces cAMP, leading to the activation of cAMP-dependent protein kinases (often referred to collectively as Protein Kinase A). The signal from the ligand-stimulated GPCR is amplified because the receptor can activate several Gs heterotrimers before it is inactivated. Another downstream effector of G alpha (s) is the protein tyrosine kinase c-Src (Ma et al. 2000).
View original pathway at:Reactome.
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Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ.; ''beta-Arrestin: a protein that regulates beta-adrenergic receptor function.''; PubMedEurope PMCScholia
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Buck L, Axel R.; ''A novel multigene family may encode odorant receptors: a molecular basis for odor recognition.''; PubMedEurope PMCScholia
The classical role of the G-protein beta/gamma dimer was believed to be the inactivation of the alpha subunit, Gbeta/gamma was viewed as a negative regulator of Galpha signalling. It is now known that Gbeta/gamma subunits can directly modulate many effectors, including some also regulated by G alpha.
The heterotrimeric guanine nucleotide-binding proteins (G-proteins) function to transduce signals from this vast panoply of receptors to effector systems including ion channels and enzymes that alter the rate of production, release or degradation of intracellular second messengers. GPCRs activate the G-proteins, which consist of an alpha-subunit that binds and hydrolyses guanosine triphosphate (GTP), a beta and a gamma subunit.
Olfactory receptors (ORs) have diverse protein sequences but can be assigned to subfamilies on the basis of sequence relationships. Odorants and pheromones bind to these seven transmembrane domain G-protein-coupled receptors that permit signal transduction. These receptors are encoded by large multigene families that evolved in mammal species in function of specific olfactory needs. Members of the same subfamily have related sequences and are likely to recognize structurally related odorants.
Of the 960 human OR genes and pseudogenes, there is experimental evidence which indicates that at least 437 actually are expressed in human olfactory epithelium; this includes 357 OR genes, and 80 OR pseudogenes (Zhang, 2007). These 357 olfactory-expressed OR genes are therefore expected to be functional in the Olfactory Signaling Pathway, and to interact directly with human G alpha olf in human olfactory cells.
(Note: A subset of 200 of these 357 OR genes are shown as components of OR-G Protein reaction. The others will be added to Reactome later.)
G(s)-alpha:GTP binds to inactive adenylate cyclase, causing a conformational transition in adenylate cyclase exposing the catalytic site and activating it.
When a ligand activates a G protein-coupled receptor, it induces a conformational change in the receptor (a change in shape) that allows the receptor to function as a guanine nucleotide exchange factor (GEF), stimulating the exchange of GDP for GTP on the G alpha subunit. In the traditional view of heterotrimeric protein activation, this exchange triggers the dissociation of the now active G alpha subunit from the beta:gamma dimer, initiating downstream signalling events. The G alpha subunit has intrinsic GTPase activity and will eventually hydrolyze the attached GTP to GDP, allowing reassociation with G beta:gamma. Additional GTPase-activating proteins (GAPs) stimulate the GTPase activity of G alpha, leading to more rapid termination of the transduced signal. In some cases the downstream effector may have GAP activity, helping to deactivate the pathway. This is the case for phospholipase C beta, which possesses GAP activity within its C-terminal region (Kleuss et al. 1994).
The liganded receptor undergoes a conformational change, generating a signal that is propagated in a manner that is not completely understood to the the G-protein. This stimulates the exchange of GDP for GTP in the G-protein alpha subunit, activating the G-protein.
This event is negatively regulated by some Activators of G protein signaling (AGS) proteins, a class of proteins identified in yeast functional screens for proteins able to activate G protein signaling in the absence of a G protein–coupled receptor (GPCR) (Cismowski et al. 1999, Takesono et al. 1999). AGS proteins contain G protein regulatory (GPR) motifs (also referred to as the GoLoco motif) that bind and stabilize the Galpha subunit in its GDP-bound conformation (Mochizuki et al. 1996, Peterson et al. 2000, Cao et al. 2004, Blumer & Lanier 2014). Some RGS proteins similarly bind to Galpha preventing the exchange of GDP for GTP (Soundararajan et al. 2008).
The heterotrimeric guanine nucleotide-binding proteins (G-proteins) function to transduce signals from this vast panoply of receptors to effector systems including ion channels and enzymes that alter the rate of production, release or degradation of intracellular second messengers. GPCRs activate the G-proteins, which consist of an alpha-subunit that binds and hydrolyses guanosine triphosphate (GTP), a beta and a gamma subunit.
Olfactory receptors (ORs) have diverse protein sequences but can be assigned to subfamilies on the basis of sequence relationships. Odorants and pheromones bind to these seven transmembrane domain G-protein-coupled receptors that permit signal transduction. These receptors are encoded by large multigene families that evolved in mammal species in function of specific olfactory needs. Members of the same subfamily have related sequences and are likely to recognize structurally related odorants.
Of the 960 human OR genes and pseudogenes, there is experimental evidence which indicates that at least 437 actually are expressed in human olfactory epithelium; this includes 357 OR genes, and 80 OR pseudogenes (Zhang, 2007). These 357 olfactory-expressed OR genes are therefore expected to be functional in the Olfactory Signaling Pathway, and to interact directly with human G alpha olf in human olfactory cells.
(Note: A subset of 200 of these 357 OR genes are shown as components of OR-G Protein reaction. The others will be added to Reactome later.)
The activation of adenylyl (adenylate) cyclase (AC) results in the production of adenosine-3',5'-monophosphate i.e. cyclic AMP. Humans have 9 genes encoding membrane-associated AC and one encoding a soluble AC. Two of the classes of heterotrimeric G-proteins are named according to their effect on AC; Gs stimulates all membrane-bound ACs (the s in Gs denotes AC stimulatory); the Gi class inhibits some AC isoforms, particularly 5 and 6. Beta-gamma subunits of heterotrimeric G-proteins can also regulate AC. Ca2+/Calmodulin activates some AC isoforms (1, 8 and 3) but is inhibitory to others (5 and 6).
Cyclic nucleotide phosphodiesterases (PDEs) are a large family of enzymes that regulate signal transduction by the second messenger molecules cAMP and cGMP. Some PDEs are cAMP selective (PDE4, 7 and 8), some cGMP selective (PDE5, 6 and 9) while others can hydrolyse cAMP and cGMP (PDE1, 2, 3, 10 and 11). PDEs are important as drug targets: Sildenafil (Viagra) is an inhibitor of PDE5; Cilostazol (Pletal) inhibits PDE3, increasing the flexibility of erythrocytes.
The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (s) and the beta:gamma dimer then participate in separate signaling cascades. Although G protein dissociation has been contested (e.g. Bassi et al. 1996), recent in vivo experiments have demonstrated that dissociation does occur, though possibly not to completion (Lambert 2008).
The role of the guanine nucleotide-binding protein G alpha-s subunit (G alpha-s) (Kozasa T et al, 1988) is to activate adenylate cyclase, which, in turn, produces cAMP, which, in turn, activates cAMP-dependent protein kinase.
The classical model of G-protein signaling suggests that the G-protein dissociates upon GPCR activation. The active alpha subunit then participates in signaling, until its intrinsic GTPase activity degrades the bound GTP to GDP. The inactive G alpha (s):GDP complex has much higher affinity for the G beta:gamma complex and consequently reassociates into the inactive heterotrimeric G-protein.
G protein-coupled receptor kinase 2 (ADRBK1, GRK2, beta-ARK), ADRBK2 (GRK3, beta-ARK2), GRK5 and GRK6 can phosphorylate activated beta-adrenergic receptors (Benovic et al. 1986a, Richardson et al. 1993, Menard et al. 1996, Violin et al. 2006). GRK2, GRK5 and GRK6 phosphorylate the beta-2 adrenergic receptor (ADRB2) in the carboxy-terminal tail region (Premont et al. 1994, 1995, Violin et al. 2006). GRK2 and GRK6 are thought to be the predominant GRKs that mediate ADRB2 desensitization (Violin et al. 2006), phosphorylating distinct serine residues (Nobles et al. 2011).
GRK phosphorylation follwed by arrestin binding and internalization is the classical model for GPCR desensitization. Many GPCRs have been demonstrated to require phosphorylation before they can bind arrestin, but other receptors do not appear to require phosphorylation in order to bind arrestin (see refs included in Gurevich & Gurevich 2006). In these receptors, spatially close acidic amino acids are thought to provide sites that can bind the arrestin phosphate sensing region. In GPCRs that require phosphorylation, the region most commonly involved in arrestin binding is the C-terminus, but many GPCRs have phosphorylation sites in the 3rd cytoplasmic loop, while in some cases phosphorylation sites are found in the first (i1) or second (i2) cytoplasmic loops (Gurevich & Gurevich 2006).
Two ubiquitously expressed forms of arrestin, arrestin-2 (ARRB1) and arrestin-3 (ARRB2), can bind and desensitize B2AR (Lohse et al. 1990, Attramadal et al. 1992, Sterne-Marr et al. 1993). Unlike visual arrestin, which has 10-fold greater affinity for phosphorylated rather than unphosphorylated rhodopsin, ARRB1 and ARRB2 show only a 2-fold difference in binding levels and are much less selective in their receptor preferences (Gurevich & Gurevich 2006). GRK-mediated receptor phosphorylation followed by arrestin binding and internalization is the classical model for GPCR desensitization. Many GPCRs have been demonstrated to require phosphorylation before they can bind arrestin, but other receptors do not appear to require phosphorylation in order to bind arrestin (see refs. included in Gurevich & Gurevich 2006). In these receptors, spatially close acidic amino acids are thought to provide sites that can bind the arrestin phosphate sensing region.
G protein-coupled receptor kinase 2 (ADRBK1, GRK2, beta-ARK), ADRBK2 (GRK3, beta-ARK2), GRK5 and GRK6 can phosphorylate activated beta-adrenergic receptors (Benovic et al. 1986a, Richardson et al. 1993, Menard et al. 1996, Violin et al. 2006). GRK2, GRK5 and GRK6 can bind and phosphorylate the beta-2 adrenergic receptor (ADRB2) in the carboxy-terminal tail region (Premont et al. 1994, 1995, Violin et al. 2006). Following this, phosphorylated ADRB2 dissociates from the ADRB2:GRK complex. GRK2 and GRK6 are thought to be the predominant GRKs that mediate ADRB2 desensitization (Violin et al. 2006), phosphorylating distinct serine residues (Nobles et al. 2011).
GRK phosphorylation follwed by arrestin binding and internalization is the classical model for GPCR desensitization. Many GPCRs have been demonstrated to require phosphorylation before they can bind arrestin, but other receptors do not appear to require phosphorylation in order to bind arrestin (see refs included in Gurevich & Gurevich 2006). In these receptors, spatially close acidic amino acids are thought to provide sites that can bind the arrestin phosphate sensing region. In GPCRs that require phosphorylation, the region most commonly involved in arrestin binding is the C-terminus, but many GPCRs have phosphorylation sites in the 3rd cytoplasmic loop, while in some cases phosphorylation sites are found in the first (i1) or second (i2) cytoplasmic loops (Gurevich & Gurevich 2006).
G protein-coupled receptor kinase 2 (ADRBK1, GRK2, beta-ARK), ADRBK2 (GRK3, beta-ARK2), GRK5 and GRK6 can phosphorylate activated beta-adrenergic receptors (Benovic et al. 1986a, Richardson et al. 1993, Menard et al. 1996, Violin et al. 2006). GRK2, GRK5 and GRK6 can bind to beta-2 adrenergic receptor (ADRB2) and subsequently phosphorylate them in the carboxy-terminal tail region (Premont et al. 1994, 1995, Violin et al. 2006). GRK2 and GRK6 are thought to be the predominant GRKs that mediate ADRB2 desensitization (Violin et al. 2006), phosphorylating distinct serine residues (Nobles et al. 2011).
GRK phosphorylation follwed by arrestin binding and internalization is the classical model for GPCR desensitization. Many GPCRs have been demonstrated to require phosphorylation before they can bind arrestin, but other receptors do not appear to require phosphorylation in order to bind arrestin (see refs included in Gurevich & Gurevich 2006). In these receptors, spatially close acidic amino acids are thought to provide sites that can bind the arrestin phosphate sensing region. In GPCRs that require phosphorylation, the region most commonly involved in arrestin binding is the C-terminus, but many GPCRs have phosphorylation sites in the 3rd cytoplasmic loop, while in some cases phosphorylation sites are found in the first (i1) or second (i2) cytoplasmic loops (Gurevich & Gurevich 2006).
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DataNodes
(s):GTP:Adenylate
cyclase(i):GTP:Adenylate
cyclase(z):GTP:Adenylate
cyclasecomplexes that act on Gs:Heterotrimeric G-protein Gs
(active)G-protein Gs
(inactive)complexes that activate Gs:Heterotrimeric G-protein Gs
(inactive)complexes that
activate GsOf the 960 human OR genes and pseudogenes, there is experimental evidence which indicates that at least 437 actually are expressed in human olfactory epithelium; this includes 357 OR genes, and 80 OR pseudogenes (Zhang, 2007). These 357 olfactory-expressed OR genes are therefore expected to be functional in the Olfactory Signaling Pathway, and to interact directly with human G alpha olf in human olfactory cells.
(Note: A subset of 200 of these 357 OR genes are shown as components of OR-G Protein reaction. The others will be added to Reactome later.)
Annotated Interactions
(s):GTP:Adenylate
cyclase(s):GTP:Adenylate
cyclase(i):GTP:Adenylate
cyclase(z):GTP:Adenylate
cyclasecomplexes that act on Gs:Heterotrimeric G-protein Gs
(active)complexes that act on Gs:Heterotrimeric G-protein Gs
(active)G-protein Gs
(inactive)G-protein Gs
(inactive)complexes that activate Gs:Heterotrimeric G-protein Gs
(inactive)complexes that activate Gs:Heterotrimeric G-protein Gs
(inactive)complexes that activate Gs:Heterotrimeric G-protein Gs
(inactive)complexes that
activate GsOf the 960 human OR genes and pseudogenes, there is experimental evidence which indicates that at least 437 actually are expressed in human olfactory epithelium; this includes 357 OR genes, and 80 OR pseudogenes (Zhang, 2007). These 357 olfactory-expressed OR genes are therefore expected to be functional in the Olfactory Signaling Pathway, and to interact directly with human G alpha olf in human olfactory cells.
(Note: A subset of 200 of these 357 OR genes are shown as components of OR-G Protein reaction. The others will be added to Reactome later.)
GRK phosphorylation follwed by arrestin binding and internalization is the classical model for GPCR desensitization. Many GPCRs have been demonstrated to require phosphorylation before they can bind arrestin, but other receptors do not appear to require phosphorylation in order to bind arrestin (see refs included in Gurevich & Gurevich 2006). In these receptors, spatially close acidic amino acids are thought to provide sites that can bind the arrestin phosphate sensing region. In GPCRs that require phosphorylation, the region most commonly involved in arrestin binding is the C-terminus, but many GPCRs have phosphorylation sites in the 3rd cytoplasmic loop, while in some cases phosphorylation sites are found in the first (i1) or second (i2) cytoplasmic loops (Gurevich & Gurevich 2006).
GRK phosphorylation follwed by arrestin binding and internalization is the classical model for GPCR desensitization. Many GPCRs have been demonstrated to require phosphorylation before they can bind arrestin, but other receptors do not appear to require phosphorylation in order to bind arrestin (see refs included in Gurevich & Gurevich 2006). In these receptors, spatially close acidic amino acids are thought to provide sites that can bind the arrestin phosphate sensing region. In GPCRs that require phosphorylation, the region most commonly involved in arrestin binding is the C-terminus, but many GPCRs have phosphorylation sites in the 3rd cytoplasmic loop, while in some cases phosphorylation sites are found in the first (i1) or second (i2) cytoplasmic loops (Gurevich & Gurevich 2006).