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.
Siderovski DP, Willard FS.; ''The GAPs, GEFs, and GDIs of heterotrimeric G-protein alpha subunits.''; PubMedEurope PMCScholia
Richardson RM, Kim C, Benovic JL, Hosey MM.; ''Phosphorylation and desensitization of human m2 muscarinic cholinergic receptors by two isoforms of the beta-adrenergic receptor kinase.''; PubMedEurope PMCScholia
Tesmer JJ, Sunahara RK, Gilman AG, Sprang SR.; ''Crystal structure of the catalytic domains of adenylyl cyclase in a complex with Gsalpha.GTPgammaS.''; PubMedEurope PMCScholia
Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ.; ''beta-Arrestin: a protein that regulates beta-adrenergic receptor function.''; PubMedEurope PMCScholia
Keller A, Zhuang H, Chi Q, Vosshall LB, Matsunami H.; ''Genetic variation in a human odorant receptor alters odour perception.''; PubMedEurope PMCScholia
Kozasa T, Itoh H, Tsukamoto T, Kaziro Y.; ''Isolation and characterization of the human Gs alpha gene.''; PubMedEurope PMCScholia
Wenzel-Seifert K, Liu HY, Seifert R.; ''Similarities and differences in the coupling of human beta1- and beta2-adrenoceptors to Gs(alpha) splice variants.''; PubMedEurope PMCScholia
Baker LP, Nielsen MD, Impey S, Metcalf MA, Poser SW, Chan G, Obrietan K, Hamblin MW, Storm DR.; ''Stimulation of type 1 and type 8 Ca2+/calmodulin-sensitive adenylyl cyclases by the Gs-coupled 5-hydroxytryptamine subtype 5-HT7A receptor.''; PubMedEurope PMCScholia
Martin AL, Steurer MA, Aronstam RS.; ''Constitutive Activity among Orphan Class-A G Protein Coupled Receptors.''; PubMedEurope PMCScholia
Oldham WM, Hamm HE.; ''Structural basis of function in heterotrimeric G proteins.''; PubMedEurope PMCScholia
Ma YC, Huang J, Ali S, Lowry W, Huang XY.; ''Src tyrosine kinase is a novel direct effector of G proteins.''; PubMedEurope PMCScholia
Graziano MP, Freissmuth M, Gilman AG.; ''Expression of Gs alpha in Escherichia coli. Purification and properties of two forms of the protein.''; PubMedEurope PMCScholia
SUTHERLAND EW, RALL TW.; ''Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles.''; PubMedEurope PMCScholia
Benovic JL, Strasser RH, Caron MG, Lefkowitz RJ.; ''Beta-adrenergic receptor kinase: identification of a novel protein kinase that phosphorylates the agonist-occupied form of the receptor.''; PubMedEurope PMCScholia
Feldman DS, Zamah AM, Pierce KL, Miller WE, Kelly F, Rapacciuolo A, Rockman HA, Koch WJ, Luttrell LM.; ''Selective inhibition of heterotrimeric Gs signaling. Targeting the receptor-G protein interface using a peptide minigene encoding the Galpha(s) carboxyl terminus.''; PubMedEurope PMCScholia
Zhang X, De la Cruz O, Pinto JM, Nicolae D, Firestein S, Gilad Y.; ''Characterizing the expression of the human olfactory receptor gene family using a novel DNA microarray.''; PubMedEurope PMCScholia
Lambert NA.; ''Dissociation of heterotrimeric g proteins in cells.''; PubMedEurope PMCScholia
Maurice DH.; ''Cyclic nucleotide phosphodiesterase-mediated integration of cGMP and cAMP signaling in cells of the cardiovascular system.''; PubMedEurope PMCScholia
Belluscio L, Gold GH, Nemes A, Axel R.; ''Mice deficient in G(olf) are anosmic.''; PubMedEurope PMCScholia
Violin JD, Ren XR, Lefkowitz RJ.; ''G-protein-coupled receptor kinase specificity for beta-arrestin recruitment to the beta2-adrenergic receptor revealed by fluorescence resonance energy transfer.''; PubMedEurope PMCScholia
Dupré DJ, Robitaille M, Rebois RV, Hébert TE.; ''The role of Gbetagamma subunits in the organization, assembly, and function of GPCR signaling complexes.''; PubMedEurope PMCScholia
Attramadal H, Arriza JL, Aoki C, Dawson TM, Codina J, Kwatra MM, Snyder SH, Caron MG, Lefkowitz RJ.; ''Beta-arrestin2, a novel member of the arrestin/beta-arrestin gene family.''; PubMedEurope PMCScholia
Mitsuhashi M, Mitsuhashi T, Payan DG.; ''Multiple signaling pathways of histamine H2 receptors. Identification of an H2 receptor-dependent Ca2+ mobilization pathway in human HL-60 promyelocytic leukemia cells.''; PubMedEurope PMCScholia
Ménard L, Ferguson SS, Barak LS, Bertrand L, Premont RT, Colapietro AM, Lefkowitz RJ, Caron MG.; ''Members of the G protein-coupled receptor kinase family that phosphorylate the beta2-adrenergic receptor facilitate sequestration.''; PubMedEurope PMCScholia
Cabrera-Vera TM, Vanhauwe J, Thomas TO, Medkova M, Preininger A, Mazzoni MR, Hamm HE.; ''Insights into G protein structure, function, and regulation.''; PubMedEurope PMCScholia
Dessauer CW, Chen-Goodspeed M, Chen J.; ''Mechanism of Galpha i-mediated inhibition of type V adenylyl cyclase.''; PubMedEurope PMCScholia
Zhang JY, Nawoschik S, Kowal D, Smith D, Spangler T, Ochalski R, Schechter L, Dunlop J.; ''Characterization of the 5-HT6 receptor coupled to Ca2+ signaling using an enabling chimeric G-protein.''; PubMedEurope PMCScholia
Oldham WM, Hamm HE.; ''Heterotrimeric G protein activation by G-protein-coupled receptors.''; PubMedEurope PMCScholia
Menashe I, Abaffy T, Hasin Y, Goshen S, Yahalom V, Luetje CW, Lancet D.; ''Genetic elucidation of human hyperosmia to isovaleric acid.''; PubMedEurope PMCScholia
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; G(s) stimulates all membrane-bound ACs (the s in G(s) denotes AC stimulatory); the G(i) 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 Receptors sense extracellular signals and activate different Guanine nucleotide binding proteins. Upon activation, the alpha subunit of the G protein (GNAS) can directly bind to SRC. In the presence of active GNAS, SRC can autophosphorylate the 416-tyrosine residue, which leads to the subsequent activation of SRC. Physiologically, the SRC family have implications in cell growth and cancer. GNAS increases SRC enzymatic activity by decreasing Km and not affecting Vm.
G-Protein Coupled Receptors (GPCR) sense extracellular signals and activate different Guanine nucleotide binding proteins. Upon activation, the Guanine nucleotide-binding protein G(s) subunit alpha (GNAS) can bind directly to proto-oncogene tyrosine-protein kinase Src (SRC) in vitro and in vivo. This binding results in autophosphorylation of SRC and subsequently its activation. Physiologically, the SRC family have implications in cell growth and cancer.
Upon autophosphorylation, SRC dissociates from GNAS and is subsequently activated. GNAS increases SRC enzymatic activity by decreasing Km and not affecting Vm. Physiologically, the SRC family have implications in cell growth and cancer.
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).
Cyclic nucleotide phosphodiesterases (PDEs) are a large family of enzymes that regulate signal transduction by the second messenger molecules cAMP and cGMP (Maurice 2005). PDEs are important as drug targets:PDE3 inhibition promotes cardiac muscle contraction, a strategy used in heart failure.
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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).