The heterotrimeric G protein G alpha (z), is a member of the G (i) family. Unlike other G alpha (i) family members it lacks an ADP ribosylation site cysteine four residues from the carboxyl terminus and is thus pertussis toxin-insensitive. It inhibits adenylyl cyclase types I, V and VI (Wong Y H et al. 1992). G alpha (z) interacts with the Rap1 GTPase activating protein (Rap1GAP) to attenuate Rap1 signaling. Like all G-proteins G alpha (z) has an intrinsic GTPase activity, but this activity tends to be lower for the pertussis toxin insensitive G-proteins, most strikingly so for G alpha (z), whose kcat value for GTP hydrolysis is 200-fold lower than those of G alpha (s) or G alpha (i) (Grazziano et al. 1989). G alpha (z) knockout mice have disrupted platelet aggregation at physiological concentrations of epinephrine and responses to several neuroactive drugs are altered (Yang et al. 2000). Regulator of G-protein Signalling (RGS) proteins can regulate the activity of G alpha (z) (Soundararajan M et al. 2008).
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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
Lambert NA.; ''Dissociation of heterotrimeric g proteins in cells.''; PubMedEurope PMCScholia
Oldham WM, Hamm HE.; ''Structural basis of function in heterotrimeric G proteins.''; PubMedEurope PMCScholia
Kleuss C, Raw AS, Lee E, Sprang SR, Gilman AG.; ''Mechanism of GTP hydrolysis by G-protein alpha subunits.''; PubMedEurope PMCScholia
Lounsbury KM, Casey PJ, Brass LF, Manning DR.; ''Phosphorylation of Gz in human platelets. Selectivity and site of modification.''; PubMedEurope PMCScholia
Wong YH, Conklin BR, Bourne HR.; ''Gz-mediated hormonal inhibition of cyclic AMP accumulation.''; PubMedEurope PMCScholia
Yang J, Wu J, Kowalska MA, Dalvi A, Prevost N, O'Brien PJ, Manning D, Poncz M, Lucki I, Blendy JA, Brass LF.; ''Loss of signaling through the G protein, Gz, results in abnormal platelet activation and altered responses to psychoactive drugs.''; PubMedEurope PMCScholia
Soundararajan M, Willard FS, Kimple AJ, Turnbull AP, Ball LJ, Schoch GA, Gileadi C, Fedorov OY, Dowler EF, Higman VA, Hutsell SQ, Sundström M, Doyle DA, Siderovski DP.; ''Structural diversity in the RGS domain and its interaction with heterotrimeric G protein alpha-subunits.''; PubMedEurope PMCScholia
Goto K, Doi M, Wang T, Kunisue S, Murai I, Okamura H.; ''G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review].''; PubMedEurope PMCScholia
Gagnon AW, Manning DR, Catani L, Gewirtz A, Poncz M, Brass LF.; ''Identification of Gz alpha as a pertussis toxin-insensitive G protein in human platelets and megakaryocytes.''; PubMedEurope PMCScholia
Fields TA, Casey PJ.; ''Phosphorylation of Gz alpha by protein kinase C blocks interaction with the beta gamma complex.''; PubMedEurope PMCScholia
Ho MK, Wong YH.; ''G(z) signaling: emerging divergence from G(i) signaling.''; PubMedEurope PMCScholia
Kach J, Sethakorn N, Dulin NO.; ''A finer tuning of G-protein signaling through regulated control of RGS proteins.''; PubMedEurope PMCScholia
Siderovski DP, Willard FS.; ''The GAPs, GEFs, and GDIs of heterotrimeric G-protein alpha subunits.''; PubMedEurope PMCScholia
Neubig RR, Siderovski DP.; ''Regulators of G-protein signalling as new central nervous system drug targets.''; PubMedEurope PMCScholia
SUTHERLAND EW, RALL TW.; ''Fractionation and characterization of a cyclic adenine ribonucleotide formed by tissue particles.''; PubMedEurope PMCScholia
Mao H, Zhao Q, Daigle M, Ghahremani MH, Chidiac P, Albert PR.; ''RGS17/RGSZ2, a novel regulator of Gi/o, Gz, and Gq signaling.''; PubMedEurope PMCScholia
Chan JS, Chiu TT, Wong YH.; ''Activation of type II adenylyl cyclase by the cloned mu-opioid receptor: coupling to multiple G proteins.''; PubMedEurope PMCScholia
Wang J, Ducret A, Tu Y, Kozasa T, Aebersold R, Ross EM.; ''RGSZ1, a Gz-selective RGS protein in brain. Structure, membrane association, regulation by Galphaz phosphorylation, and relationship to a Gz gtpase-activating protein subfamily.''; 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.
G-proteins in the Gi class inhibit adenylate cyclase activity, decreasing the production of cAMP from ATP, which has many consequences but classically results in decreased activity of Protein Kinase A (PKA). cAMP also activates the cyclic nucleotide-gated ion channels, a process that is particularly important in olfactory cells. Experimental data for this reaction was obtained in vitro using rat G alpha (i) and dog Adenylate Cyclase.
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).
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).
Gz is predominantly expressed in the nervous system and platelets. Gz interacts with receptors for many neurotransmitters and neuropeptides, including the adenosine A1, alpha2-adrenergic, dopamine D2, 5-HT1A, muscarinic M2, substance P, and all types of opioid receptors. In addition, Gz is capable of transducing signals from receptors such as the C5a and formyl peptide receptors. All these receptors can also signal via Gi. (Ho & Wong 2001).
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 classical model of G-protein signaling suggests that the G-protein dissociates upon GPCR activation. The active G alpha (z) subunit then participates in signaling, until its intrinsic GTPase activity degrades the bound GTP to GDP. The inactive G alpha (z):GDP complex has much higher affinity for the G beta:gamma complex and consequently reassociates.
The classical view of G-protein signalling is that the G-protein alpha subunit dissociates from the beta:gamma dimer. Activated G alpha (z) 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).
G alpha z (Lounsbury et al. 1991) and G alpha 12 (Kozasa & Gilman, 1996) are excellent in vitro substrates for all three subtypes of protein kinase C (PKC). Activation of PKC in intact platelets by agents such as thrombin, thromboxane A2 (TXA2) analogues and phorbol esters leads to rapid and near-stoichiometric phosphorylation of G alpha z (Carlson et al. 1989). The primary phosphorylation site is Ser-27 (Lounsbury et al. 1993). This phosphorylation blocks the interaction of G alpha z with Gbeta:gamma suggesting that it is a regulatory mechanism for attenuating signalling by preventing subunit reassociation.
G Protein Coupled Receptors (GPCR) sense extracellular signals and activate different Guanine nucleotide binding proteins (G proteins). Upon activation, GPCRs can replace the GDP with GTP in the alpha subunit of G proteins. GTP binding modifies the conformation of G alpha proteins and activates them. The Regulator of G protein Signalling (RGS) are GTPase Accelerating Proteins (GAPs) that can directly inhibit the G alpha subunit activity. There are at least 25 different types of RGS proteins known. RGS16, RGS17 and RGS20 can bind and stabilize the transition state of Guanine nucleotide binding protein G(z) subunit alpha (GNAZ) along its path to GTP hydrolysis. Subsequently, this leads to GTP hydrolysis and inactivation of GNAZ, terminating downstream signalling (Neubig & Siderovski 2002, Kach et al. 2012, Goto K et al. 2017). GNAZ inhibits adenylyl cyclase and interacts with Rap1GAP to attenuate Rap1 signaling.
G Protein Coupled Receptors (GPCR) sense extracellular signals and activate different Guanine nucleotide binding proteins (G proteins). Upon activation, GPCRs can replace the GDP with GTP in the alpha subunit of G proteins. GTP binding modifies the conformation of G alpha proteins and activates them. The Regulator of G protein Signalling (RGS) are GTPase Accelerating Proteins (GAPs) that can directly inhibit the G alpha subunit activity. There are at least 25 different types of RGS proteins known. RGS16, RGS17 and RGS20 can bind and stabilize the transition state of Guanine nucleotide binding protein G(z) subunit alpha (GNAZ). Subsequently, RGS proteins in the complex facilitate the hydrolysis of GNAZ:GTP to GNAZ:GDP. Following this, the complex dissociates releasing inactive GNAZ ((Neubig & Siderovski 2002, Kach et al. 2012, Goto K et al. 2017). GNAZ inhibits adenylyl cyclase and interacts with Rap1GAP to attenuate Rap1 signaling.
G Protein Coupled Receptors (GPCR) sense extracellular signals and activate different Guanine nucleotide binding proteins (G proteins). Upon activation, GPCRs can replace the GDP with GTP in the alpha subunit of G proteins. GTP binding modifies the conformation of G alpha proteins and activates them. The Regulator of G protein Signalling (RGS) are GTPase Accelerating Proteins (GAPs) that can directly inhibit the G alpha subunit activity. There are at least 25 different types of RGS proteins known. RGS16, RGS17 and RGS20 can bind and stabilize the transition state of Guanine nucleotide binding protein G(z) subunit alpha (GNAZ). Following this, RGS exerts its GAP activity on GNAZ and facilitates the hydrolyses GTP to GDP. This inactivates GNAZ and terminates downstream signalling (Neubig & Siderovski 2002, Kach et al. 2012, Goto K et al. 2017). GNAZ inhibits adenylyl cyclase and interacts with Rap1GAP to attenuate Rap1 signaling.
G alpha z (Lounsbury et al. 1991) and G alpha 12 (Kozasa & Gilman, 1996) are excellent in vitro substrates for all three subtypes of protein kinase C (PKC). Activation of PKC in intact platelets by agents such as thrombin, thromboxane A2 (TXA2) analogues and phorbol esters leads to rapid and near-stoichiometric phosphorylation of G alpha z (Carlson et al. 1989). PKC can bind to G alpha z and facilitate its phosphorylation at Ser-27 (Lounsbury et al. 1993). This phosphorylation blocks the interaction of G alpha z with Gbeta:gamma suggesting that it is a regulatory mechanism for attenuating signalling by preventing subunit reassociation.
G alpha z (Lounsbury et al. 1991) and G alpha 12 (Kozasa & Gilman, 1996) are excellent in vitro substrates for all three subtypes of protein kinase C (PKC). Activation of PKC in intact platelets by agents such as thrombin, thromboxane A2 (TXA2) analogues and phorbol esters leads to rapid and near-stoichiometric phosphorylation of G alpha z (Carlson et al. 1989). PKC can bind to G alpha z and facilitate phosphorylation at Ser-27 (Lounsbury et al. 1993). Subsequently, phosphorylated G alpha z dissociates from the complex. This phosphorylation blocks the interaction of G alpha z with Gbeta:gamma suggesting that it is a regulatory mechanism for attenuating signalling by preventing subunit reassociation.
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DataNodes
(s):GTP:Adenylate
cyclase(i):GTP:Adenylate
cyclase(z):GTP:Adenylate
cyclaseG-protein Gz
(inactive)complexes that activate Gz:Heterotrimeric G-protein Gz
(inactive)conventional and
novel isoformsAnnotated Interactions
(s):GTP:Adenylate
cyclase(z):GTP:Adenylate
cyclase(z):GTP:Adenylate
cyclaseG-protein Gz
(inactive)G-protein Gz
(inactive)complexes that activate Gz:Heterotrimeric G-protein Gz
(inactive)complexes that activate Gz:Heterotrimeric G-protein Gz
(inactive)complexes that activate Gz:Heterotrimeric G-protein Gz
(inactive)conventional and
novel isoformsconventional and
novel isoforms