Gene Report

Basic Information

Approved Symbol	GNAS
Approved Name	GNAS complex locus
Previous Symbol	GNAS1
Previous Name	"guanine nucleotide binding protein (G protein), alpha stimulating activity polypeptide 1"
Symbol Alias	NESP55, NESP, GNASXL, GPSA, SCG6
Name Alias	"secretogranin VI"
Location	20q13.2-q13.3
Position	chr20:57485885-57486247 (+)
External Links	Entrez Gene: 2778 Ensembl: ENSG00000087460 UCSC: uc002xzw.3 HGNC ID: 4392
No. of Studies (Positive/Negative)	1(0/1)
Type	Literature-origin

Positive relationships between GNAS and MDD (count: 0)

Positive relationships between GNAS and other components at different levels (count: 0)

Positive relationship network of GNAS in MK4MDD

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Note:
1. The different color of the nodes denotes the level of the nodes.

Genetic/Epigenetic Locus	Protein and Other Molecule	Cell and Molecular Pathway	Neural System	Cognition and Behavior	Symptoms and Signs	Environment	MDD

2. Besides the component related relationships from literature, gene mapped protein and protein mapped gene are also shown in the network. If the mapped gene or protein is not from literature, square node would be used instead of Circle node. Accordingly, the relationship is marked with dot line.
2. User can drag the nodes to rearrange the layout of the network. Click the node will enter the report page of the node. Right-click will show also the menus to link to the report page of the node and remove the node and related edges. Hover the node will show the level of the node and hover the edge will show the evidence/description of the edge.
3. The network is generated using Cytoscape Web

Negative relationships between GNAS and MDD (count: 1)

Name in Literature	Reference	Research Type	Statistical Result	Relation Description
stimulatory alpha subunit of G-proteins	Zill P, 2002	Patients and nomal controls		There was no evidence for an association between the invest...... There was no evidence for an association between the investigated polymorphism in the G(alpha)(s) gene and major depression, as well as to treatment response. More...

Negative relationships between GNAS and other components at different levels (count: 0)

GNAS related SNPs in MK4MDD (count: 0)

GNAS related proteins in MK4MDD (count: 0)

GNAS related GO terms (count: 75)

ID	Name	Type	Evidence
Literature-origin GO terms
GO:0004016	adenylate cyclase activity	molecular function	TAS

ID	Name	Type	Evidence
Gene mapped GO terms
GO:0043547	positive regulation of GTPase activity	biological process	IDA[12391161]
GO:0050796	regulation of insulin secretion	biological process	TAS
GO:0016020	membrane	cellular component	IDA[12719376\|19946888]; ISS
GO:0009966	regulation of signal transduction	biological process	IMP[12719376]
GO:0003674	molecular_function	molecular function	ND
GO:0032553	ribonucleotide binding	molecular function	IEA
GO:0001894	tissue homeostasis	biological process	IEA
GO:0032553	ribonucleotide binding	molecular function	IEA
GO:0001726	ruffle	cellular component	IEA
GO:0006306	DNA methylation	biological process	IEA
GO:0032553	ribonucleotide binding	molecular function	IEA
GO:0030133	transport vesicle	cellular component	IEA
GO:0071107	response to parathyroid hormone	biological process	IMP[22378814]
GO:0055085	transmembrane transport	biological process	TAS
GO:0071377	cellular response to glucagon stimulus	biological process	TAS
GO:0071870	cellular response to catecholamine stimulus	biological process	ISS
GO:0003924	GTPase activity	molecular function	IEA; TAS[9159128]
GO:0070527	platelet aggregation	biological process	IDA[12719376]; IMP[12719376]
GO:0031748	D1 dopamine receptor binding	molecular function	IBA
GO:0050890	cognition	biological process	IDA[12719376]; IMP[12719376]
GO:0031683	G-protein beta/gamma-subunit complex binding	molecular function	IEA
GO:0045669	positive regulation of osteoblast differentiation	biological process	IEA
GO:0071880	adenylate cyclase-activating adrenergic receptor signaling pathway	biological process	IDA[12391161]
GO:0035116	embryonic hindlimb morphogenesis	biological process	IEA
GO:0001958	endochondral ossification	biological process	IEA
GO:0051216	cartilage development	biological process	IEA
GO:0035255	ionotropic glutamate receptor binding	molecular function	IBA
GO:0051430	corticotropin-releasing hormone receptor 1 binding	molecular function	IBA
GO:0042493	response to drug	biological process	IEA
GO:0046872	metal ion binding	molecular function	IEA
GO:0031224	intrinsic component of membrane	cellular component	IDA[7997272]
GO:0043950	positive regulation of cAMP-mediated signaling	biological process	IDA[12391161]
GO:0048701	embryonic cranial skeleton morphogenesis	biological process	IEA
GO:0030425	dendrite	cellular component	IEA
GO:0032588	trans-Golgi network membrane	cellular component	IDA[7997272]
GO:0005515	protein binding	molecular function	IPI[12719376\|20852621\|22177524\|23353685]
GO:0070062	extracellular exosome	cellular component	IDA[19199708\|20458337\|23376485\|23533145]
GO:0007189	adenylate cyclase-activating G-protein coupled receptor signaling pathway	biological process	IDA[12719376\|17110384]; IMP[12719376]
GO:0060348	bone development	biological process	IDA[12719376]; IMP[12719376]
GO:0032553	ribonucleotide binding	molecular function	IEA
GO:0007608	sensory perception of smell	biological process	TAS[3018580]
GO:0006833	water transport	biological process	TAS
GO:0005834	heterotrimeric G-protein complex	cellular component	ISS; TAS[9159128]
GO:0035264	multicellular organism growth	biological process	IEA
GO:0007596	blood coagulation	biological process	TAS
GO:0006171	cAMP biosynthetic process	biological process	TAS
GO:0030819	positive regulation of cAMP biosynthetic process	biological process	IDA[12391161]
GO:0048471	perinuclear region of cytoplasm	cellular component	IDA[21584660]
GO:0005737	cytoplasm	cellular component	IDA[20862257]
GO:0004871	signal transducer activity	molecular function	IDA[12391161]; IEA
GO:0007190	activation of adenylate cyclase activity	biological process	TAS[9159128]
GO:0007565	female pregnancy	biological process	NAS[10729789]
GO:0005634	nucleus	cellular component	IDA[20862257]
GO:0003091	renal water homeostasis	biological process	TAS
GO:0031698	beta-2 adrenergic receptor binding	molecular function	IBA
GO:0007191	adenylate cyclase-activating dopamine receptor signaling pathway	biological process	IBA; ISS
GO:0071380	cellular response to prostaglandin E stimulus	biological process	ISS
GO:0040032	post-embryonic body morphogenesis	biological process	IEA
GO:0045672	positive regulation of osteoclast differentiation	biological process	IEA
GO:0006112	energy reserve metabolic process	biological process	IEA; TAS
GO:0005886	plasma membrane	cellular component	IEA; TAS[9727013]
GO:0009306	protein secretion	biological process	NAS[10729789]
GO:0044281	small molecule metabolic process	biological process	TAS
GO:0005576	extracellular region	cellular component	IEA
GO:0048589	developmental growth	biological process	IDA[12719376]; IMP[12719376]
GO:0031852	mu-type opioid receptor binding	molecular function	IBA
GO:0005525	GTP binding	molecular function	IEA
GO:0046907	intracellular transport	biological process	NAS[7997272]
GO:0071514	genetic imprinting	biological process	IEA
GO:0060789	hair follicle placode formation	biological process	IDA[12719376]; IMP[12719376]
GO:0005829	cytosol	cellular component	IDA[12719376]; ISS
GO:0005159	insulin-like growth factor receptor binding	molecular function	IBA
GO:0040015	negative regulation of multicellular organism growth	biological process	ISS
GO:0007606	sensory perception of chemical stimulus	biological process	IBA

GNAS related KEGG pathways (count: 10)

ID	Name	Brief Description	Full Description
Literature-origin KEGG pathway
hsa04020	calcium signaling_pathway	Calcium signaling pathway	Ca2+ that enters the cell from the outside is a principal so...... Ca2+ that enters the cell from the outside is a principal source of signal Ca2+. Entry of Ca2+ is driven by the presence of a large electrochemical gradient across the plasma membrane. Cells use this external source of signal Ca2+ by activating various entry channels with widely different properties. The voltage-operated channels (VOCs) are found in excitable cells and generate the rapid Ca2+ fluxes that control fast cellular processes. There are many other Ca2+-entry channels, such as the receptor-operated channels (ROCs), for example the NMDA (N-methyl-D-aspartate) receptors (NMDARs) that respond to glutamate. There also are second-messenger-operated channels (SMOCs) and store-operated channels (SOCs). The other principal source of Ca2+ for signalling is the internal stores that are located primarily in the endoplasmic/sarcoplasmic reticulum (ER/SR), in which inositol-1,4,5-trisphosphate receptors (IP3Rs) or ryanodine receptors (RYRs) regulate the release of Ca2+. The principal activator of these channels is Ca2+ itself and this process of Ca2+-induced Ca2+ release is central to the mechanism of Ca2+ signalling. Various second messengers or modulators also control the release of Ca2+. IP3, which is generated by pathways using different isoforms of phospholipase C (PLCbeta, delta, epsilon, gamma and zeta), regulates the IP3Rs. Cyclic ADP-ribose (cADPR) releases Ca2+ via RYRs. Nicotinic acid adenine dinucleotide phosphate (NAADP) may activate a distinct Ca2+ release mechanism on separate acidic Ca2+ stores. Ca2+ release via the NAADP-sensitive mechanism may also feedback onto either RYRs or IP3Rs. cADPR and NAADP are generated by CD38. This enzyme might be sensitive to the cellular metabolism, as ATP and NADH inhibit it. The influx of Ca2+ from the environment or release from internal stores causes a very rapid and dramatic increase in cytoplasmic calcium concentration, which has been widely exploited for signal transduction. Some proteins, such as troponin C (TnC) involved in muscle contraction, directly bind to and sense Ca2+. However, in other cases Ca2+ is sensed through intermediate calcium sensors such as calmodulin (CALM). More...
hsa04730	long term_depression	Long-term depression	Cerebellar long-term depression (LTD), thought to be a molec...... Cerebellar long-term depression (LTD), thought to be a molecular and cellular basis for cerebellar learning, is a process involving a decrease in the synaptic strength between parallel fiber (PF) and Purkinje cells (PCs) induced by the conjunctive activation of PFs and climbing fiber (CF). Multiple signal transduction pathways have been shown to be involved in this process. Activation of PFs terminating on spines in dendritic branchlets leads to glutamate release and activation of both AMPA and mGluRs. Activation of CFs, which make multiple synaptic contacts on proximal dendrites, also via AMPA receptors, opens voltage-gated calcium channels (VGCCs) and causes a generalized influx of calcium. These cellular signals, generated from two different synaptic origins, trigger a cascade of events culminating in a phosphorylation-dependent, long-term reduction in AMPA receptor sensitivity at the PF-PC synapse. This may take place either through receptor internalization and/or through receptor desensitization. More...
hsa04270	vascular smooth_muscle_contraction	Vascular smooth muscle contraction	The vascular smooth muscle cell (VSMC) is a highly specializ...... The vascular smooth muscle cell (VSMC) is a highly specialized cell whose principal function is contraction. On contraction, VSMCs shorten, thereby decreasing the diameter of a blood vessel to regulate the blood flow and pressure. The principal mechanisms that regulate the contractile state of VSMCs are changes in cytosolic Ca2+ concentration (c). In response to vasoconstrictor stimuli, Ca2+ is mobilized from intracellular stores and/or the extracellular space to increase c in VSMCs. The increase in c, in turn, activates the Ca2+-CaM-MLCK pathway and stimulates MLC20 phosphorylation, leading to myosin-actin interactions and, hence, the development of contractile force. The sensitivity of contractile myofilaments or MLC20 phosphorylation to Ca2+ can be secondarily modulated by other signaling pathways. During receptor stimulation, the contractile force is greatly enhanced by the inhibition of myosin phosphatase. Rho/Rho kinase, PKC, and arachidonic acid have been proposed to play a pivotal role in this enhancement. The signaling events that mediate relaxation include the removal of a contractile agonist (passive relaxation) and activation of cyclic nucleotide-dependent signaling pathways in the continued presence of a contractile agonist (active relaxation). Active relaxation occurs through the inhibition of both Ca2+ mobilization and myofilament Ca2+ sensitivity in VSMCs. More...

ID	Name	Brief Description	Full Description
Gene mapped KEGG pathways
hsa04916	melanogenesis	Melanogenesis	Cutaneous melanin pigment plays a critical role in camouflag...... Cutaneous melanin pigment plays a critical role in camouflage, mimicry, social communication, and protection against harmful effects of solar radiation. Melanogenesis is under complex regulatory control by multiple agents. The most important positive regulator of melanogenesis is the MC1 receptor with its ligands melanocortic peptides. MC1R activates the cyclic AMP (cAMP) response-element binding protein (CREB). Increased expression of MITF and its activation by phosphorylation (P) stimulate the transcription of tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerase (DCT), which produce melanin. Melanin synthesis takes place within specialized intracellular organelles named melanosomes. Melanin-containing melanosomes then move from the perinuclear region to the dendrite tips and are transferred to keratinocytes by a still not well-characterized mechanism. More...
hsa04540	gap junction	Gap junction	Gap junctions contain intercellular channels that allow dire...... Gap junctions contain intercellular channels that allow direct communication between the cytosolic compartments of adjacent cells. Each gap junction channel is formed by docking of two 'hemichannels', each containing six connexins, contributed by each neighboring cell. These channels permit the direct transfer of small molecules including ions, amino acids, nucleotides, second messengers and other metabolites between adjacent cells. Gap junctional communication is essential for many physiological events, including embryonic development, electrical coupling, metabolic transport, apoptosis, and tissue homeostasis. Communication through Gap Junction is sensitive to a variety of stimuli, including changes in the level of intracellular Ca2+, pH, transjunctional applied voltage and phosphorylation/dephosphorylation processes. This figure represents the possible activation routes of different protein kinases involved in Cx43 and Cx36 phosphorylation. More...
hsa04912	gnrh signaling_pathway	GnRH signaling pathway	Gonadotropin-releasing hormone (GnRH) secretion from the hyp...... Gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus acts upon its receptor in the anterior pituitary to regulate the production and release of the gonadotropins, LH and FSH. The GnRHR is coupled to Gq/11 proteins to activate phospholipase C which transmits its signal to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG activates the intracellular protein kinase C (PKC) pathway and IP3 stimulates release of intracellular calcium. In addition to the classical Gq/11, coupling of Gs is occasionally observed in a cell-specific fashion. Signaling downstream of protein kinase C (PKC) leads to transactivation of the epidermal growth factor (EGF) receptor and activation of mitogen-activated protein kinases (MAPKs), including extracellular-signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 MAPK. Active MAPKs translocate to the nucleus, resulting in activation of transcription factors and rapid induction of early genes. More...
hsa04962	vasopressin regulated_water_reabsorption	Vasopressin-regulated water reabsorption	In the kidney, the antidiuretic hormone vasopressin (AVP) is...... In the kidney, the antidiuretic hormone vasopressin (AVP) is a critical regulator of water homeostasis by controlling the water movement from lumen to the interstitium for water reabsorption and adjusting the urinary water excretion. In normal physiology, AVP is secreted into the circulation by the posterior pituitary gland, in response to an increase in serum osmolality or a decrease in effective circulating volume. When reaching the kidney, AVP binds to V2 receptors on the basolateral surface of the collecting duct epithelium, triggering a G-protein-linked signaling cascade, which leads to water channel aquaporin-2 (AQP2) vesicle insertion into the apical plasma membrane. This results in higher water permeability in the collecting duct and, driven by an osmotic gradient, pro-urinary water then passes the membrane through AQP2 and leaves the cell on the basolateral side via AQP3 and AQP4 water channels, which are constitutively expressed on the basolateral side of these cells. When isotonicity is restored, reduced blood AVP levels results in AQP2 internalization, leaving the apical membrane watertight again. More...
hsa05414	dilated cardiomyopathy	Dilated cardiomyopathy	Dilated cardiomyopathy (DCM) is a heart muscle disease chara...... Dilated cardiomyopathy (DCM) is a heart muscle disease characterised by dilation and impaired contraction of the left or both ventricles that results in progressive heart failure and sudden cardiac death from ventricular arrhythmia. Genetically inherited forms of DCM (familial DCM) have been identified in 25-35% of patients presenting with this disease, and the inherited gene defects are an important cause of familial DCM. The pathophysiology may be separated into two categories: defects in force generation and defects in force transmission. In cases where an underlying pathology cannot be identified, the patient is diagnosed with an idiopathic DCM. Current hypotheses regarding causes of idiopathic DCM focus on chronic viral myocarditis and/or on autoimmune abnormalities. Viral myocarditis may progress to an autoimmune phase and then to progressive cardiac dilatation. Antibodies to the beta1-adrenergic receptor (beta1AR), which are detected in a substantial number of patients with idiopathic DCM, may increase the concentration of intracellular cAMP and intracellular Ca2+, a condition often leading to a transient hyper-performance of the heart followed by depressed heart function and heart failure. More...
hsa05110	vibrio cholerae_infection	Vibrio cholerae infection	Cholera toxin (CTX) is one of the main virulence factors of ...... Cholera toxin (CTX) is one of the main virulence factors of Vibrio cholerae. Once secreted, CTX B-chain (CTXB) binds to ganglioside GM1 on the surface of the host's cells. After binding takes place, the entire CTX complex is carried from plasma membrane (PM) to endoplasmic reticulum (ER). In the ER, the A-chain (CTXA) is recognized by protein disulfide isomerase (PDI), unfolded, and delivered to the membrane where the membrane-associated ER-oxidase, Ero1, oxidizes PDI to release the CTXA into the protein-conducting channel, Sec61. CTXA is then retro-translocated to the cytosol and induces water and electrolyte secretion by increasing cAMP levels via adenylate cyclase (AC) to exert toxicity. Other than CTX, Vibrio cholerae generates several toxins that are perilous to eukaryotic cells. Zonula occludens toxin (ZOT) causes tight junction disruption through protein kinase C-dependent actin polymerization. RTX toxin (RtxA) causes actin depolymerization by covalently cross-linking actin monomers into dimers, trimers, and higher multimers. Vibrio cholerae cytolysin (VCC) is an important pore-forming toxin. The assembly of VCC anion channels in cells cause vacuolization and lysis. More...
hsa04742	taste transduction	Taste transduction	All taste pathways are proposed to converge on common elemen...... All taste pathways are proposed to converge on common elements that mediate a rise in intracellular Ca2+ followed by neurotransmitter release. Na+ salt depolarizes taste cells by passive influx of Na+ through the amiloride-sensitive Na+ channel (ENaC). Acids depolarize taste cells by a variety of mechanisms, including influx of protons (H+) through ENaC and a proton-gated cation channel (MDEG). Two putative umami receptors have been identified: a truncated variant of the metabotropic glutamate receptor mGluR4 and the heterodimer, T1R1 + T1R3. Umami receptors are coupled to a signaling pathway involving activation of PLCbeta2, production of IP3 and diacylglycerol, release of Ca2+ from intracellular stores and activation of a transient receptor potential channel, TRPM5. Bitter compounds, such as denatonium and PROP, activate particular T2R/TRB isoforms, which activate gustducin heterotrimers. Activated alpha-gustducin stimulates PDE to hydrolyze cAMP, whereas betagamma subunits activate PLCbeta2 to generate IP3, which leads to release of Ca2+ from internal stores. Artificial sweeteners activate GPCRs (T1R heterodimers) apparently linked via PLC to IP3 production and release of Ca2+ from intracellular stores. Sugars apparently activate GPCRs linked via AC to cAMP production which, in turn, may inhibit basolateral K+ channels through phosphorylation by cAMP-activated protein kinase A (PKA). More...

GNAS related BioCarta pathways (count: 13)

ID	Name	Brief Description	Full Description
Gene mapped BioCarta pathways
BARR_MAPK_PATHWAY	barr mapk_pathway	Role of fl-arrestins in the activation and targeting of MAP kinases	The binding of -arrestins to agonist-occupied GPCRs triggers...... The binding of -arrestins to agonist-occupied GPCRs triggers the assembly of a MAP kinase activation complex using -arrestin as a scaffold, with subsequent activation of a -arrestin-bound pool of ERK1/2. The receptor-arrestinERK complexes are localized to endosomal vesicles, and their formation does not result in nuclear translocation of activated ERK1/2 or stimulation of cell proliferation. The function of -arrestin-bound ERK1/2 is presently unknown. Activation of ERK1/2 by -arrestin scaffolds may favor the phosphorylation of plasma membrane, cytosolic, or cytoskeletal ERK1/2 substrates, or it may lead to transcriptional activation through the ERK-dependent activation of other kinases. The model depicts -arrestin scaffolding of the ERK1/2 MAP kinase cascade, based upon data obtained with the protease-activated PAR2 and angiotensin AT1a receptors. A similar mechanism has been proposed for regulation of the JNK3 MAP kinase cascade by AT1a receptors. More...
CREB_PATHWAY	creb pathway	Transcription factor CREB and its extracellular signals	The transcription factor CREB binds the cyclic AMP response ...... The transcription factor CREB binds the cyclic AMP response element (CRE) and activates transcription in response to a variety of extracellular signals including neurotransmitters, hormones, membrane depolarization, and growth and neurotrophic factors. Protein kinase A and the calmodulin-dependent protein kinases CaMKII stimulate CREB phosphorylation at Ser133, a key regulatory site controlling transcriptional activity. Growth and neurotrophic factors also stimulate CREB phosphorylation at Ser133. Phosphorylation occurs at Ser133 via p44/42 MAP Kinase and p90RSK and also via p38 MAP Kinase and MSK1. CREB exhibit deficiencies in spatial learning tasks, while flies overexpressing or lacking CREB show enhanced or diminished learning, respectively. More...
PLCE_PATHWAY	plce pathway	Phospholipase C-epsilon pathway	Proposed model for b2-AR- and prostanoid-receptor-mediated P...... Proposed model for b2-AR- and prostanoid-receptor-mediated PLC and calcium signalling. Receptors coupling to Gs stimulate AC, resulting in elevated cAMP levels and activation of Epac1. Epac1 then catalyses GTP-loading on Rap2B, which leads to PLC-e activation. The proposed pathway may involve additional signalling components to attain PLC stimulation. The action of cAMP seems to be independent of PKA; Instead, the cAMP-activated Rap-GEF Epac seems to serve as a cAMP effector, inducing GTP loading and, hence, activation of Rap2B, which then leads to specific activation of PLC-e, which has been shown to interact with Rap GTPases. It is an attractive hypothesis, therefore, that the Rap-dependent PLC and calcium signalling pathway reported here is not restricted to Gs-and AC-coupled receptors, such as the b2-AR and the prostanoid receptor, but could be used by other receptors as well. More...
CCR3_PATHWAY	ccr3 pathway	CCR3 signaling in Eosinophils	Eosinophils are a key class of leukocytes involved in inflam...... Eosinophils are a key class of leukocytes involved in inflammatory responses, including allergic reactions in skin and airway. The eosinophil response in inflammation is absent in mice lacking CCR3, indicating the key role of this G protein coupled receptor in inflammation and allergic responses. Eotaxin is a chemokine ligand for CCR3 that recruits eosinophils to the site of inflammation and activates them. Other chemokine ligands of CCR3 include eotaxin-2, MCP-3, MCP-4, and RANTES. Multiple signaling pathways activated by CCR3 participate in the inflammatory response of eosinophils. Eotaxin stimulates intracellular calcium release, production of reactive oxygen species, and changes in actin polymerization through a pertussis sensitive pathway. Rho and ROCK regulate actin stress fiber formation and are required for eosinophil chemotaxis. Rho is a G protein that activates ROCK, a protein kinase. Map kinase pathways are also involved in chemotaxis. Another key action of activated eosinophils is the release of reactive oxygen species, causing tissue damage during chronic inflammatory responses. Blocking eosinophil activation and the signaling pathways that lead to chemotaxis, degranulation and reactive oxygen release may alleviate inflammatory conditions and inflammation-associated tissue damage. More...
BARRESTIN_SRC_PATHWAY	barrestin src_pathway	Roles of fl-arrestin-dependent Recruitment of Src Kinases in GPCR Signaling	The binding of -arrestins to agonist-occupied GPCRs coincide...... The binding of -arrestins to agonist-occupied GPCRs coincides with the recruitment of Src family tyrosine kinases, including c-Src, Hck and c-Fgr (Src-TK), to the receptor-arrestin complex. Several signaling events have been reported to involve -arrestin-dependent Src recruitment. These include the regulation of clathrin-dependent 2-adrenergic receptor endocytosis by tyrosine phosphorylation of dynamin, Ras-dependent activation of the ERK1/2 MAP kinase cascade and stimulation of cell proliferation by 2-adrenergic and neurokinin NK1 receptors, and stimulation of chemokine CXCR1 receptor-mediated neutrophil degranulation More...
BARRESTIN_PATHWAY	barrestin pathway	fl-arrestins in GPCR Desensitization	Role of -arrestins in the desensitization, sequestration and...... Role of -arrestins in the desensitization, sequestration and intracellular trafficking of GPCRs. Homologous desensitization of GPCRs (1) results from the binding of -arrestins (-arr) to agonist -occupied receptors following phosphorylation of the receptor by GRKs. -arrestin binding sterically precludes coupling between the receptor and heterotrimeric G proteins, leading to termination of signaling by G proteins effectors. Receptor-bound -arrestins also act as adapter proteins, binding to components of the clathrin endocytic machinery including clathrin, 2-adaptin (AP-2). Receptor sequestration (2) reflects the dynamin (Dyn)-dependent endocytosis of GPCRs via clathrin-coated pits. Once internalized, GPCRs exhibit two distinct patterns of -arrestin interaction. `Class A' GPCRs, for example the 2 adrenergic receptor, rapidly dissociate from -arrestin upon internalization. These receptors are trafficked to an acidified endosomal compartment, wherein the ligand is dissociated and the receptor dephosphorylated by a GPCR-specific protein phosphatase PP2A isoform, and are subsequently recycled to the plasma membrane (3). `Class B' receptors, for example the angiotensin II AT1a receptor, form stable receptor--arrestin complexes. These receptors accumulate in endocytic vesicles and are either targeted for degradation or slowly recycled to the membrane via as yet poorly defined routes. More...
CSK_PATHWAY	csk pathway	Activation of Csk by cAMP-dependent Protein Kinase Inhibits Signaling through the T Cell Receptor	Interaction of T cell receptor with specific antigen in the ...... Interaction of T cell receptor with specific antigen in the context of MHC II activates a signal transduction pathway that leads to T cell activation. In the T cell receptor signaling pathway, the src family kinases Lck and Fyn are activated to phosphorylate proteins in the T cell receptor complex which recruit and activate the ZAP70 kinase. The activation of ZAP70 phosphorylates downstream targets that activate MAP kinase pathways and cause T cell activation. The CD45 phosphorylase also plays a role in T cell receptor signaling, dephosphorylated Lck and Fyn to activate them. Other factors modulate T cell receptor activation. Csk (COOH-terminal Srk kinase) phosphorylates Lck and deactivates it, opposing the action of CD45. The phosphorylation of Lck by Csk inhibits T cell receptor signaling and inhibits T cell activation. Csk activity is regulated in T cells by PKA, the cAMP-dependent protein kinase activated by the second messenger cAMP. The activity of Csk also appears to depend on other factors such as CBP, which recruits Csk to the plasma membrane in lipid rafts where other signaling factors such the T cell receptor complex are localized. CBP also directly activates Csk. More...
GPCR_PATHWAY	gpcr pathway	Signaling Pathway from G-Protein Families	G-aS-coupled receptors stimulate adenylyl cyclase (AC), whic...... G-aS-coupled receptors stimulate adenylyl cyclase (AC), which synthesizes cAMP from ATP. In contrast Gai-coupled receptors inhibit AC and so reduce cAMP formation. The bg subunits from Gai and other G proteins are able to activate the MAP kinase pathways and PLCb. GPCRs coupled to the Gaq family of G proteins stimulate PLCb, which cleaves membrane phospholipids to produce IP3, which mobilizes intracellular calcium, and DAG, which activates PKC. Second messenger pathways then activate a range of effector systems to change cell behaviour; in many cases this includes the regulation of gene transcription. Dotted line shows a more indirect pathway. More...
AGPCR_PATHWAY	agpcr pathway	Attenuation of GPCR Signaling	The G-protein coupled receptor (GPCR) family transduces extr...... The G-protein coupled receptor (GPCR) family transduces extracellular signals across the plasma membrane, activating cellular responses through a variety of second messenger cascades. These receptors provide rapid responses to a variety of stimuli, and are often rapidly attenuated in their signaling. Failure to attenuate GPCR signaling can have dramatic consequences. One method to attenuate GPCR signaling is by removal of the stimulus from the extracellular fluid. At the synapse, removal of neurotransmitter or peptide signaling molecules is accomplished by either reuptake or degradation. Acetylcholine is removed from synapses through degradation by the enzyme acetylcholinesterase. Inhibition of acetylcholinesterase results in prolonged signaling at the neuromuscular junction, and uncontrollable spasms in humans caused by nerve gas or in insects by some insecticides. Inhibition of acetylcholinesterase is also used therapeutically to treat Alzheimer's disease, compensating for the loss of cholinergic neurons. Transporters for serotonin, dopamine, GABA and noradrenaline remove these neurotransmitters from the synapse to terminate signaling. Antidepressants such as Prozac inhibit reuptake of serotonin and many drugs of abuse such as cocaine act by blocking reuptake of dopamine or adrenaline. Reuptake not only terminates signaling, but can also conserve neurotransmitter through recycling back into the presynaptic cell. The next step in the attenuation of GPCR signaling is receptor desensitization, in which receptors are modified to no longer transduce a signal even if the stimulus is still present. Desensitization of GPCRs occurs through protein kinases that phosphorylate the GPCR to turn off signaling. Downstream protein kinases such as PKA and PKC turned on by GPCR signaling can phosphorylate the activated GPCR and other GPCRs to prevent further signaling. G-protein receptor kinases (GRKs) are a family of kinases that specifically phosphorylate only agonist-occupied GPCRs. GRKs attenuate GPCR signaling in concert with arrestins, proteins that bind GRK-phosphorylated GPCRs to disrupt interaction with G-protein and to terminate signaling. Reducing the number of receptor expressed on the cell surface can also attenuate receptor signaling. Many GPCRs are removed from the cell surface by receptor-mediated endocytosis when they are activated. Endocytosis of activated GPCRs appears to be stimulated by GRKs and arrestins. Once internalized, receptors can either be degraded in lysosomes or they can be recycled back to the cell surface. More...
MPR_PATHWAY	mpr pathway	How Progesterone Initiates Oocyte Membrane	Progesterone (Pg) binds to both intracellular iPR and plasma...... Progesterone (Pg) binds to both intracellular iPR and plasma membrane- bound mPR. (Right Top) After binding to Pg, iPR is recruited to the membrane associated protein tyrosine kinase p60c- src, which induces activation of the MAPK signaling pathway. This results in activation of p90Rsk and the subsequent phosphorylation and inactivation of Myt1, which favors formation of the activated cell cycle complex cyclin B-Cdc2. Activation of cyclin B-Cdc2 causes breakdown of the germinal vesicle and the initiation of oocyte maturation. (Left). In contrast, binding of Pg to mPR leads to inhibition of adenylyl cyclase (AC) through activation of Gi or inhibition of Gs. This leads to a decrease in the cAMPdependent kinase PKA, which relieves inhibition of Cdc25C (the phosphatase that dephosphorylates and activates cyclin B-Cdc2) and also indirectly promotes the activation of MAPK signaling. PKA also regulates the initiation of oocyte maturation through other effects that are independent of PKA activity. More...
CFTR_PATHWAY	cftr pathway	Cystic Fibrosis Transmembrane Conductance Regulator And Beta 2 Adrenergic Receptor Pathway	The defects in cAMP-regulated chloride channel CTFR are beli...... The defects in cAMP-regulated chloride channel CTFR are believed to be the major cause for cystic fibrosis. Regulation of CFTR protein by the surface receptor beta adrenergic receptor is mediated through the ezrin/radixin/moesin binding phosphoprotein 50 (EBP50), which binds both the C-termini CFTR and b2AR through their PDZ binding motifs. In the resting state, CFTR, b2AR, and EBP50 exist as a macromolecular complex on the apical surface of epithelial cells. Upon agonist activation of the b2AR, the adenulate cyclase is stimulated through the G protein pathway, leading to an increase in cAMP. The elevated concentration of cAMP activates PKA, which is anchored near CFTR via interaction with Ezrin. The phosphorylation of CFTR by PKA disrupts the complex and leads to compartmentalized and specific signaling of the channel. More...
GCR_PATHWAY	gcr pathway	Corticosteroids and cardioprotection	Myocardial infarction damages heart tissue both during the i...... Myocardial infarction damages heart tissue both during the initial ischemia and the subsequent reperfusion of tissues with oxygen. Corticosteroids can protect cardiac tissue from damage following a heart attack, but the mechanisms by which corticosteroids are cardioprotective have not been clear and negative side effects such as reduced wound healing may result from their use. Corticosteroids exert a variety of actions through binding to the glucocorticoid receptor (GR), a member of the steroid hormone receptor gene family. GR acts as a ligand-dependent transcription factor, but some of the cardioprotective effects mediated by GR-bound corticosteroids are non-transcriptional in nature. Glucocorticoids are commonly used as anti-inflammatory drugs in a variety of conditions, and some of their effects in the heart result from inhibition of the inflammatory response of heart tissue to ischemia and reperfusion. NF-kB is a transcription factor involved in signaling by inflammatory factors such as TNF, and is repressed by glucocorticoids. Annexin-1 is a calcium-dependent phospholipid binding protein whose expression is induced by corticosteroids and inhibits the infiltration of neutrophils into tissue, blocking reperfusion-induced inflammatory heart damage. A non-transcriptional cardioprotective effect of glucocorticoids is activation of NO production by endothelial nitric oxide synthase (eNOS). Glucocorticoids activate eNOS through activation of PI3 kinase and AKT and increased NO produced by eNOS can diffuse into surrounding tissues to prevent clotting and cause vasodilation. The beta-2 adrenergic receptor can also activate PI3 kinase and may synergize with glucocorticoids in this pathway. The atrial natriuretic factor (ANF) is a peptide secreted by the atrial wall in response to increased atrial pressure such as occurs during cardiac failure and to be decreased by myocardial infarction. Glucocorticoids increase the secretion of ANF by acting at the transcriptional level to increase expression of the pro-ANF peptide, perhaps inducing increased water excretion in the kidneys to reduce blood volume and reduce atrial pressure. The exploration of glucorticoid responses may allow the identification of compounds that retain the cardioprotective activities but do not inhibit wound healing. Alternative mechanisms of eNOS activation may also provide a route to identify cardioprotective drugs. More...
ERK_PATHWAY	erk pathway	Erk1/Erk2 Mapk Signaling pathway	The p44/42 MAP Kinase pathway consists of a protein kinase c...... The p44/42 MAP Kinase pathway consists of a protein kinase cascade linking growth and differentiation signals with transcription in the nucleus. Growth factor receptors and tyrosine kinases activate Ras which in turn activates c-Raf, MEK, and MAP kinase. Activated p44/42 MAP Kinase translocates to the nucleus and activates transcription by phosphorylation of kinases such as p90 RSK, MSK, and transcription factors such as ELK-1 and Stat3. The importance of this pathway in both growth control and development has been demonstrated via the transforming properties of various mutant forms of Ras, Raf, MEK and by their effects on development. Signal amplification and the potential for crosstalk appear to be important features of this regulatory network. More...

GNAS related Reactome pathways (count: 11)

ID	Name	Description
Gene mapped Reactome pathways
REACT_1161	gs alpha_mediated_events_in_glucagon_signalling	Guanine nucleotide binding proteins or G proteins constitute...... Guanine nucleotide binding proteins or G proteins constitute a large family of proteins that transmit signals from membrane receptors to downstream effector molecules. Each G protein is composed of 3 subunits: alpha, beta and gamma. The alpha subunit binds to guanine nucleotide and is important for receptor coupling and effector activation. Each of s, i and q - forms of the alpha subunit has a functional specificity. About 4 isoforms of the beta subunit are known. Of the 12 subunits of gamma subunits known so far, subunits 1 and 9 are active in photoreceptor coupled signalling while others are expressed in various tissues. The beta and gamma subunits occur as dimers on the cell surface and the specific role, tissue occurrence and the binding preferences between isoforms of these subunits are still being unraveled. More...
REACT_18274	regulation of_insulin_secretion_by_glucagon_like_peptide_1	Glucagon-like Peptide-1 (GLP-1) is secreted by L-cells in th...... Glucagon-like Peptide-1 (GLP-1) is secreted by L-cells in the intestine in response to glucose and fatty acids. GLP-1 circulates to the beta cells of the pancreas where it binds a G-protein coupled receptor, GLP-1R, on the plasma membrane. The binding activates the heterotrimeric G-protein G(s), causing the alpha subunit of G(s) to exchange GDP for GTP and dissociate from the beta and gamma subunits. The activated G(s) alpha subunit interacts with Adenylyl Cyclase VIII (Adenylate Cyclase VIII, AC VIII) and activates AC VIII to produce cyclic AMP (cAMP). cAMP then has two effects: 1) cAMP activates Protein Kinase A (PKA), and 2) cAMP activates Epac1 and Epac2, two guanyl nucleotide exchange factors. Binding of cAMP to PKA causes the catalytic subunits of PKA to dissociate from the regulatory subunits and become an active kinase. PKA is known to enhance insulin secretion by closing ATP-sensitive potassium channels, closing voltage-gated potassium channels, releasing calcium from the endoplasmic reticulum, and affecting insulin secretory granules. The exact mechanisms for PKA's action are not fully known. After prolonged increases in cAMP, PKA translocates to the nucleus where it regulates the PDX-1 and CREB transcription factors, activating transcription of the insulin gene. cAMP produced by AC VIII also activates Epac1 and Epac2, which catalyze the exchange of GTP for GDP on G-proteins, notably Rap1A.. Rap1A regulates insulin secretory granules and is believed to activate the Raf/MEK/ERK mitogenic pathway leading to proliferation of beta cells. The Epac proteins also interact with RYR calcium channels on the endoplasmic reticulum, the SUR1 subunits of ATP-sensitive potassium channels, and the Piccolo:Rim2 calcium sensor at the plasma membrane. More...
REACT_19327	g alpha_s_signalling_events	The general function of the G alpha (s) subunit (Gs) is to a...... The general function of the G alpha (s) subunit (Gs) is to activate adenylate cyclase, 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. More...
REACT_1665	glucagon signaling_in_metabolic_regulation	Glucagon and insulin are peptide hormones released from the ...... Glucagon and insulin are peptide hormones released from the pancreas into the blood, that normally act in complementary fashion to stabilize blood glucose concentration. When blood glucose levels rise, insulin release stimulates glucose uptake from the blood, glucose breakdown. More...
REACT_18325	regulation of_insulin_secretion	Pancreatic beta cells integrate signals from several metabol...... Pancreatic beta cells integrate signals from several metabolites and hormones to control the secretion of insulin. In general, glucose triggers insulin secretion while other factors can amplify or inhibit the amount of insulin secreted in response to glucose. Factors which increase insulin secretion include the incretin hormones Glucose-dependent insulinotropic polypeptide (GIP and glucagon-like peptide-1 (GLP-1), acetylcholine, and fatty acids. Factors which inhibit insulin secretion include adrenaline and noradrenaline. More...
REACT_19184	downstream events_in_gpcr_signaling	G protein-coupled receptors. The beta:gamma G-protein dimer ...... G protein-coupled receptors. The beta:gamma G-protein dimer is also involved in downstream signaling , and some receptors form part of metastable complexes of receptor and accessory proteins such as the arrestins. GPCRs are involved in many diverse signaling events , using a variety of pathways that include modulation of adenylyl cyclase, phospholipase C, the mitogen activated protein kinases (MAPKs), extracellular signal regulated kinase (ERK) c-Jun-NH2-terminal kinase (JNK) and p38 MAPK. More...
REACT_15380	diabetes pathways
REACT_18377	glucagon type_ligand_receptors	The glucagon hormone family regulates the activity of GPCRs ...... The glucagon hormone family regulates the activity of GPCRs from the secretin receptor subfamily in Class II/B. More...
REACT_1505	integration of_energy_metabolism	Many hormones that affect individual physiological processes...... Many hormones that affect individual physiological processes including the regulation of appetite, absorption, transport, and oxidation of foodstuffs influence energy metabolism pathways. While insulin mediates the storage of excess nutrients, glucagon is involved in the mobilization of energy resources in response to low blood glucose levels, principally by stimulating hepatic glucose output. Small doses of glucagon are sufficient to induce significant glucose elevations. These hormone-driven regulatory pathways enable the body to sense and respond to changed amounts of nutrients in the blood and demands for energy. Glucagon and Insulin act through various metabolites and enzymes that target specific steps in metabolic pathways for sugar and fatty acids. The processes responsible for the long-term control of fat synthesis and short term control of glycolysis by key metabolic products and enzymes are annotated in this module as six specific pathways: Pathway 1. Glucagon signalling in metabolic pathways: In response to low blood glucose, pancreatic alpha-cells release glucagon. The binding of glucagon to its receptor results in increased cAMP synthesis, and Protein Kinase A - Copyright National Academy of Sciences, U.S.A.). More...
REACT_21340	gpcr ligand_binding	There are more than 800 G-protein coupled receptor. GPCRs ar...... There are more than 800 G-protein coupled receptor. GPCRs are receptors for a diverse range of ligands from large proteins to photons and have an equal diverstiy of ligand-binding mechanisms. Classical GPCR signaling involves signal transduction via heterotrimeric G-proteins, however many G-protein independent mechanisms have been reported. More...
REACT_18372	class b2_secretin_family_receptors	This family is known as Family B. This family is known as Family B.

GNAS related interactors from protein-protein interaction data in HPRD (count: 24)

Gene	Interactor	Interactor in MK4MDD?	Experiment Type	PMID
GNAS	VIPR1	No	in vitro	11812005
GNAS	AVPR2	No	in vivo	8621513
GNAS	ADCY5	No	in vitro	9268375
GNAS	RIC8A	No	in vitro;in vivo;yeast 2-hybrid	12652642
GNAS	ADRB3	No	in vivo	8011597
GNAS	ADORA1	No	in vivo	10521440
GNAS	NUCB1	No	yeast 2-hybrid	9647645
GNAS	SNX13	No	in vitro	11729322
GNAS	GCGR	No	in vivo	1908089
GNAS	PTGDR	No	in vivo	12672054
GNAS	GNGT1	No	in vitro	15368366
GNAS	RGS2	No	in vitro	9794454
GNAS	PTGIR	No	in vitro	12488443
GNAS	TSHR	No	in vitro	9525885
GNAS	RIC8B	No	in vitro;yeast 2-hybrid	12652642
GNAS	CRHR1	Yes	in vivo	10598591
GNAS	ADCY6	No	in vitro	9228084
GNAS	GNAS	Yes	in vivo	10598591
GNAS	CAV3	No	in vitro	7797570
GNAS	LHB	No	in vitro	8663226
GNAS	TTC1	No	in vitro	12748287
GNAS	HTR6	No	in vitro	11916537
GNAS	LHCGR	No	in vivo	10493819
GNAS	ADCY2	No	in vitro	9268375

Gene Report

Literature-origin GO terms

Gene mapped GO terms

Literature-origin KEGG pathway

Gene mapped KEGG pathways

Gene mapped BioCarta pathways

Gene mapped Reactome pathways