Disease relevance of Gs

• We have also shown that acidosis stimulates activation of Gs trimeric protein and CREB phosphorylation [1].
• In the present studies we investigated the kinetics of Gs dissociation and membrane release in plasma membranes from S49 lymphoma cells [2].
• In conclusion, the kinetics of adenosine receptors suggest that at early stage of peritonitis, the A(1)R dominates, and later its dominance is replaced by the G stimulatory (Gs) protein-coupled A(2A)R that suppresses inflammation [3].
• 3. The effect of (-)-isoproterenol was abolished by cholera toxin treatment, indicating the involvement of a Gs protein, whereas pertussis toxin treatment did not exhibit a current reduction [4].
• Reconstitution of the Gs protein from B16 melanoma clones of high and low experimental metastatic potential into S49 cyc-membranes [5].

High impact information on Gs

• Agonists for several Gs-protein-coupled receptors, including cell-surface adenosine purinergic receptors, can increase levels of immunosuppressive cyclic AMP in immune cells; however, it was unknown whether any of these receptors regulates inflammation in vivo [6].
• Activation of the Gs-coupled serotonin 5-HT(4) receptor initiates this signalling cascade in various cell types [7].
• In this study, we report that immunoreactive Gs protein alpha-subunits (Gs alpha) localize to nuclei of proliferating C2C12 myoblasts but not to nuclei of differentiated postmitotic C2C12 myotubes [8].
• Regulation of meiotic prophase arrest in mouse oocytes by GPR3, a constitutive activator of the Gs G protein [9].
• In neonatal cardiac myocytes, beta1AR activates the conventional Gs/cAMP pathway, whereas beta2AR sequentially activates both the Gs and Gi pathways to regulate the myocyte contraction rate [10].

Chemical compound and disease context of Gs

• Opioid-induced APD prolongation appears to be mediated by excitatory opioid receptors that are positively coupled via a cholera toxin-A-sensitive Gs protein to adenylate cyclase/cyclic AMP-dependent ion conductances, whereas opioid-induced APD shortening is mediated by inhibitory receptors linked via pertussis toxin-sensitive Gi/Go proteins [11].
• We have investigated the influence of cholera toxin (CTX), a Gs-protein activator, and pertussis toxin (PTX), a Gi-protein inhibitor on the chronotropic interaction between higenamine and a muscarinic agonist, acetylcholine (ACh) in the isolated right atria of mice [12].

Biological context of Gs

• ICaL was stimulated by isoproterenol in the presence of a PKA inhibitor and GTP-gamma-S in LDS but not VEDS cardiomyocytes, suggesting the development of a membrane-delimited stimulatory pathway mediated through the stimulatory GTP binding protein, Gs [13].
• Down-regulation but not up-regulation could be fully mimicked by Gs-protein activation and partially by elevation of cellular cAMP [14].
• These data indicate that constitutive beta3AR coupling to Gi proteins serves both to restrain Gs-mediated activation of adenylyl cyclase and to initiate additional signal transduction pathways, including the ERK1/2 MAP kinase cascade [15].
• An activating missense mutation of the alpha subunit of the Gs protein (Gs alpha) was found in several affected tissues, resulting in prolonged stimulation of adenylate cyclase [16].
• Microinjection of a dominant negative form of Gs into Xenopus and mouse oocytes, or microinjection of an antibody that inhibits the Gs G protein into zebrafish oocytes, caused meiosis to resume [17].

Anatomical context of Gs

• Total cyclic AMP (cAMP) levels were reduced in Ep2-/- mammary glands suggesting that PGE2 signaling via the EP2 receptor activates the Gs/cAMP/protein kinase A pathway [18].
• We have examined the mechanism and functional consequences of dual Gs/Gi protein coupling of the beta3-adrenergic receptor (beta3AR) in 3T3-F442A adipocytes [15].
• Gs protein-coupled adenosine receptor signaling and lytic function of activated NK cells [19].
• The 45-kDa alpha subunit of the signal transducing Gs protein complex, which stimulates receptor-coupled adenylate cyclase, incorporated less of the photoaffinity probe, 8N3-[gamma-32P]GTP, in extracts from tumorigenic cell lines in comparison with nontumorigenic cell lines derived from mouse lung epithelium [20].
• Mg2+ ions were obligatorily required for isoprenaline-induced dissociation of Gs in plasma membranes and for membrane release of alpha s [2].

Associations of Gs with chemical compounds

• Cutting edge: Physiologic attenuation of proinflammatory transcription by the Gs protein-coupled A2A adenosine receptor in vivo [21].
• Phorbol 12,13-dibutyrate synergistically enhanced the stimulation of both type VII and type II enzyme activity by PGE1 and by the constitutively active Gs mutant Gs (Q227L) [22].
• Experiments involving cyc- mutants (lacking the Gs-alpha protein) and 2',5'-dideoxyadenosine indicate that increased adenylate cyclase activity with swelling is not mediated by Gs [23].
• Epinephrine activates both Gs and Gi pathways, but norepinephrine activates only the Gs pathway through human beta2-adrenoceptors overexpressed in mouse heart [24].
• The plasma membranes contained 19.3 +/- 1.4 pmol of alpha s/mg of membrane protein and lacked significant dissociation of Gs and activity of adenylate cyclase in the absence of guanine nucleotides [2].

Physical interactions of Gs

• High levels of expression of functional EP4 receptors coupled with Gs-protein was confirmed in C3L5 cells by biochemical assay showing a dose-dependent increase of intracellular cAMP synthesis in response to PGE2 [25].
• The third intracellular loop of the rat gonadotropin-releasing hormone receptor couples the receptor to Gs- and G(q/11)-mediated signal transduction pathways: evidence from loop fragment transfection in GGH3 cells [26].
• The beta2-AR couples to Gs and Gi proteins [27].

Regulatory relationships of Gs

• ZnCl(2) alone stimulated signaling through the Gs pathway with a potency of 11 and 13 microm and an efficacy of 50 and 20% of that of alpha-melanocortin stimulating hormone (alpha-MSH) in the MC1 and MC4 receptors, respectively [28].
• Moreover, stimulation of Gs-proteins with cholera toxin and adenylyl cyclase with forskolin and dibutyryl-cAMP dramatically downregulated AQPap mRNA [29].
• Taken together, we demonstrate that TIMP-1 expression and secretion are selectively upregulated in adipocytes by beta-adrenergic agonists via a classic Gs-protein-coupled pathway [30].

Other interactions of Gs

• In contrast with native beta 2ARs and Gs, the receptor and the alpha s subunit moieties of the beta 2AR/Gs alpha fusion protein did not undergo functional uncoupling [31].
• These data indicate that the third intracellular loop of the rat GnRH-R is involved in receptor G(q/11) protein coupling and/or selectivity, and in the GGH(3)1' cell line, this loop is also involved in signal transduction mediated through the Gs protein pathway [26].
• Paradoxically, loop 3i from the M1Ach-muscarinic receptor also maximally inhibited GnRH agonist-stimulated cAMP accumulation and PRL release by 40% (both effects mediated through activation of the Gs protein) [26].
• 6. These results suggest that beta(3)-AR caused phosphorylation of p38 MAPK via Gs protein and partly through a pathway involving PKA and src-family kinase(s), although the contribution of the unidentified pathway remains to be clarified [32].
• Thus, PKC-alpha appears to be involved in the regulation of beta-adrenergic receptor coupling to adenylate cyclase, possibly by phosphorylating the Gs protein, but other PKC isotypes must be involved in the effects observed when cells are treated with cholera toxin [33].

Analytical, diagnostic and therapeutic context of Gs

• Despite this marked increase in mRNA, Western blotting identified only a 2.8-fold increase in the content of the Gs alpha short isoform, whereas Gs activity was increased by 88% [34].
• Cholera toxin, an agent that impairs the function of Gs transducer proteins, was injected (0.5 microgram/mouse, icv) and the antinociceptive activity of opioids and clonidine was studied 24h later in the tail-flick test [35].
• Cholera toxin (0.5 microgram/mouse, i.c.v.), agent that impairs the receptor regulation of Gs transducer proteins promoted comparable changes in the supraspinal analgesia induced by these substances [36].

References