ライフサイエンスコーパス: Galpha

1 ns that deactivate G protein alpha subunits (Galpha).

2 tail helps organize the GTP-binding site of Galpha.

3 II to stabilize the nucleotide-free state of Galpha.

4 e mutant mice that lacked both Galpha(q) and Galpha(11) selectively in SKM showed severe deficits in

5 ges lacking both Gnaq (Galpha(q)) and Gna11 (Galpha(11)) or both Gna12 (Galpha(12)) and Gna13 (Galpha

6 e were created lacking uterine Galpha(q) and Galpha(11); as a result, signaling by all uterine Galpha

7 The Galpha(12) and Galpha(13) subtypes together form the lea

8 35 and that selection between Galpha(13) and Galpha(12) is dictated largely by a single conservative

9 ined that selectivity between Galpha(13) and Galpha(12) was imbued largely by a single leucine-to-iso

10 ha(q)) and Gna11 (Galpha(11)) or both Gna12 (Galpha(12)) and Gna13 (Galpha(13)) had essentially norma

11 spectively), but not of the G(12/13) family (Galpha(12)) in the absence of post-translational phospho

12 ion of signaling profiles on the Galpha(i1), Galpha(12), and beta-arrestin2 pathways reveals the impo

13 uple efficiently to Galpha(13) but weakly to Galpha(12).

14 Incorporating Galpha(12)/Galpha(13) chimeras and individual residue sw

15 are stimulated downstream of Gbetagamma and Galpha(12/13) or Galpha(q), respectively.

16 KO mice of another Galpha(12/13)-coupling LPA receptor, LPA(6), also showed

17 esponse was weakened in KO mice of LPA(4), a Galpha(12/13)-coupling LPA receptor.

18 r-associated hotspot mutations in Arg-200 of Galpha(13) (encoded by GNA13) as potent activators of on

19 action with GPR35 and that selection between Galpha(13) and Galpha(12) is dictated largely by a singl

20 ese sensors defined that selectivity between Galpha(13) and Galpha(12) was imbued largely by a single

21 Moreover, Galpha(13) Arg-200 mutants induced oncogenic transformat

22 at are suppressed by Galpha(13), identifying Galpha(13) as a critical cytoskeletal regulator in osteo

23 For example, Galpha(13) binding to the RGS-homology (RH) domains of s

24 has been suggested to couple efficiently to Galpha(13) but weakly to Galpha(12).

25 Incorporating Galpha(12)/Galpha(13) chimeras and individual residue swap mutation

26 hermore, the significant correlation between Galpha(13) expression levels, TNF activity and RA diseas

27 a previously unrecognized role for G-protein Galpha(13) in inhibition of osteoclast adhesion, fusion

28 Deficiency of Galpha(13) in myeloid osteoclast lineage (Galpha(13)(Del

29 for mitochondrial biogenesis and function by Galpha(13) in osteoclasts.

30 nd activated RhoA, known to be downstream of Galpha(13) Intriguingly, PRG DH/PH also induced filopodi

31 These studies demonstrate that Galpha(13) is markedly the most effective G protein for

32 se activity in RA patients suggests that the Galpha(13) mediated mechanisms represent attractive ther

33 In summary, our findings on Galpha(13) mutants establish that naturally occurring ho

34 The Galpha(12) and Galpha(13) subtypes together form the least studied grou

35 of Galpha(13) in myeloid osteoclast lineage (Galpha(13)(DeltaM/DeltaM) mice) leads to super spread mo

36 d with an osteoporotic bone phenotype in the Galpha(13)(DeltaM/DeltaM) mice.

37 a(11)) or both Gna12 (Galpha(12)) and Gna13 (Galpha(13)) had essentially normal chemotaxis, Ca(2+) si

38 keleton related genes that are suppressed by Galpha(13), identifying Galpha(13) as a critical cytoske

39 way alterations were mutations in Arg-200 of Galpha(13), which we validated to promote YAP/TAZ-depend

40 P2RY8 is a Galpha(13)-coupled receptor that mediates the inhibition

41 dinated mechanism prioritizes Galpha(q)- and Galpha(13)-mediated signaling to Rho over a Gbetagamma-d

42 we confirmed marked selectivity of GPR35 for Galpha(13).

43 GTPase-deficient Galpha(q)QL and Galpha(13)QL variants formed stable complexes with Gbeta

44 his pathway was inhibited by Galpha(q)QL and Galpha(13)QL, which also prevented CXCR4-dependent cell

45 Pulldown assays revealed that chimeric Galpha(13-i2)QL interacts with Gbetagamma unlike to Galp

46 Genetic deletion of Gna15 (Galpha(15)) virtually abolished C5a-induced Ca(2+) trans

47 of alpha, beta, and gamma subunits, with 16 Galpha, 5 Gbeta and 12 Ggamma subunits.

48 ntial regulator of G protein alpha-subunits (Galpha), acting as a guanine nucleotide exchange factor

49 ndent regulator of G protein alpha-subunits (Galpha), acting as a guanine nucleotide exchange factor

50 sis mutants lacking specific combinations of Galpha and Gbeta genes, performed extensive phenotypic a

51 he signal-dependent interactions between the Galpha and Gbeta proteins.

52 odels and time-lapse microscopy to elucidate Galpha and Gbeta subunits contributing to complement C5a

53 assay with purified components revealed that Galphas and Galphai are direct substrates of DHHC5.

54 energic stimulation led to rapidly increased Galphas and Galphai palmitoylation.

55 tes heterotrimeric G protein alpha subunits (Galpha) and serves as an essential Galpha chaperone.

56 ession depended on its ability to deactivate Galpha, as overexpression of a biochemically inactive va

57 Ric-8A engages a specific conformation of Galpha at multiple interfaces to form a complex that is

58 nt of the signal-transducing alpha5-helix of Galpha away from its beta-sheet core.

59 Ric-8A binds to the exposed Galpha beta sheet and switch II to stabilize the nucleot

60 y coupling to the heterotrimeric G proteins, Galpha*betagamma Classic pharmacological methods, such a

61 on within a Ric-8A segment that connects two Galpha binding sites.

62 oup of cytoplasmic regulators that contain a Galpha-binding and -activating (GBA) motif and whose dys

63 This function is mediated by a Galpha-binding-and-activating (GBA) motif that was acqui

64 nobody-stabilized complex of nucleotide-free Galpha bound to phosphorylated Ric-8A at near atomic res

65 ration and photo-manipulation of the crucial Galpha C terminus, to demonstrate the temporal coupling

66 Additionally, they show that the Galpha C-terminus binds to a highly-conserved patch on t

67 can act as a molecular switch, driving GPCR-Galphas-cAMP signaling toward activation of EPAC-RAP1 an

68 ation of the MAPK pathway downstream of GPCR-Galphas-cAMP signaling, we show that the expression leve

69 subunits (Galpha) and serves as an essential Galpha chaperone.

70 A model of the Ric8A/Galpha complex derived from crosslinking mass spectromet

71 ls and fungi, the exchange of GDP for GTP on Galpha controls G protein activation and is crucial for

72 rk has highlighted the beneficial effects of Galphas-coupled GPCRs on reducing fibroblast activation

73 f 30 human GPCRs and their 300 possible GPCR-Galpha coupling combinations.

74 increasing GPCR gene copy number potentiates Galpha coupling of the pharmacologically dark receptor G

75 ylation pattern influences both arrestin and Galphas coupling, suggesting an additional way the cells

76 In the present study, two Galpha encoding genes (BjuA.Galpha1 and BjuB.Galpha1) we

77 c moieties were designed and found to act as Galphas enhancers while minimally activating beta-arrest

78 d establishes RhoGEF coupling as a universal Galpha function.

79 is enzyme is necessary for palmitoylation of Galphas, Galphai, and functional responses downstream of

80 e proposed regulators, including G proteins (Galphas, Galphai, Galphao, Gbetagamma), protein kinases

81 c G protein complex, consisting of canonical Galpha, Gbeta and Ggamma subunits, is involved in transd

82 Heterotrimeric G-protein (Galpha, Gbeta and Ggamma) are key signal transducers, we

83 meric G protein, each of which consists of a Galpha, Gbeta, and Ggamma subunit, making it difficult t

84 olves heterotrimeric G-proteins comprised of Galpha, Gbeta, and Ggamma subunits, which influence many

85 alian genomes encode 20 canonical RGS and 16 Galpha genes with key roles in physiology and disease.

86 G-protein coupled receptor 1 (GCR1) with the Galpha (GPA1) remained unknown.

87 The Galphas-GPCR complex detected with Nb37 displayed higher

88 oded, unimolecular biosensors for endogenous Galpha-GTP and free Gbetagamma: the two active species o

89 curs independently of the Galpha (q/11)- and Galpha (i)-signaling pathways and is dependent on signal

90 RGS6 and RGS9 are key regulators of D(2)R-Galpha (i/o) signaling in SNc DA neurons and striatal me

91 of DA loss by suppressing M(4)-autoreceptor-Galpha (i/o) signaling in striatal cholinergic interneur

92 cture of the complex of Ric8A with minimized Galpha(i) (miniGalpha(i)) in solution by small-angle X-r

93 ells showed that RGS6 prefers Galpha(o) over Galpha(i) as a substrate for its catalytic activity and

94 ver that C5a(pep) acts as a full agonist for Galpha(i) coupling as measured by cAMP response and extr

95 norbinaltorphimine (norBNI) and JDTic blocks Galpha(i) protein activation, but the signaling mechanis

96 that cross-talk between GIV, Galpha(s), and Galpha(i) proteins dampens ligand-stimulated cAMP dynami

97 ct nucleotide exchange on G proteins besides Galpha(i) remain to be investigated.

98 nd-engaged chemoattractant receptors trigger Galpha(i) subunit nucleotide exchange, stimulating the a

99 inding Galpha subunits of the G(i/o) family (Galpha(i)) over other families (such as G(s), G(q/11), o

100 data show C terminus peptides of Galpha(s), Galpha(i), and Galpha(q) proteins assume a small ensembl

101 splays constitutive signaling via Galpha(q), Galpha(i), and Galpha(s) proteins.

102 show that DAPLE's GBA motif, in addition to Galpha(i), binds efficiently to members of the G(s) and

103 ucleotide-exchange acceleration observed for Galpha(i), DAPLE inhibited nucleotide exchange on Galpha

104 rom blood in a CCR2-dependent but G protein (Galpha(i), Galpha(s) or Galpha(q/11))-independent manner

105 Several Galpha(i)-coupled G-protein-coupled receptors have been

106 G protein betagamma subunits from activated Galpha(i)-Gbetagamma heterotrimers.

107 We find that the Galpha(i)-Gbetagamma-PLCbeta-Ca(2+) signaling module is

108 dings reveal the critical interdependence of Galpha(i)-linked signaling pathways in controlling B lym

109 DOPr agonists stimulated the recruitment of Galpha(i/o) and beta-arrestin1/2 to endosomes.

110 receptor D(2) whose differential coupling to Galpha(i/o) family members has been extensively studied.

111 Recent studies showed that Galpha(i/o)-coupled GPCRs inhibit TRPM3 through a direct

112 Morphine stimulation of MOR activates a Galpha(i/o)-Gbetagamma-protein kinase C (PKC) alpha phos

113 ses 1 and 2 by Gbetagamma, Galpha(q/11), and Galpha(i/o)-independent mechanisms.

114 ins whereas M(4) transduction occurs through Galpha(i/o)-type G proteins.

115 ide are full agonists for the recruitment of Galpha(i1) but are partial agonists for Galpha(o), that

116 activity of ropinirole is biased in favor of Galpha(i1) recruitment, and that the agonist activity of

117 In a D(2)-Galpha(i1) versus D(2)-Galpha(o) screening, we retrieved

118 haracterization of signaling profiles on the Galpha(i1), Galpha(12), and beta-arrestin2 pathways reve

119 deficient (Gnai2 (-/-)) and RGS-insensitive Galpha(i2) (Gnai2 (G184S/G184S)) BMDMs.

120 Galpha(i2) ablation had minimal impact on M(2)R-GIRK and

121 complement C5a-mediated chemotaxis requires Galpha(i2) and Gbeta(2), but not Ca(2+) signaling, and m

122 regulation stems from the biased polarity of Galpha(i2) deficient (Gnai2 (-/-)) and RGS-insensitive G

123 flammatory (M1) phenotype, Gnai2(-/-) BMDMs (Galpha(i2) deficient) are biased toward alternatively ac

124 We report that Galpha(i2) in murine bone marrow-derived macrophages (BM

125 lly modified mice to investigate the role of Galpha(i2) on inflammasome activity and macrophage polar

126 t although Gnai2 (G184S/G184S) BMDMs (excess Galpha(i2) signaling) have a tendency toward classically

127 trial/SAN-selective ablation of Galpha(o) or Galpha(i2) was consistent with these findings.

128 ished in macrophages lacking Gnai2 (encoding Galpha(i2)), consistent with a reduced leukocyte recruit

129 Galpha(i2)-deficient macrophages also exhibit increased

130 Understanding Galpha(i2)-mediated effects on macrophage polarization m

131 , the reciprocal chimera, which similarly to Galpha(i2)QL could not interact with Gbetagamma.

132 13-i2)QL interacts with Gbetagamma unlike to Galpha(i2-13)QL, the reciprocal chimera, which similarly

133 ai2 (-/-) mice, whereas cells lacking Gnai3 (Galpha(i3)) exhibited only a slight decrease in cell vel

134 Artificial microRNA-based suppression of Galpha in both species resulted in similar phenotypes.

135 pha subunit of the Gs heterodimeric protein (GalphaS) into wild-type oocytes phenocopied the MIHR mut

136 The C-terminus of Galpha is ejected from its beta sheet core, thereby dism

137 , over-expression of a constitutively active Galpha, lacking the GTPase activity, produced plants wit

138 In contrast, Galpha(o) ablation decreased the amplitude and slowed th

139 e impact of atrial/SAN-selective ablation of Galpha(o) or Galpha(i2) was consistent with these findin

140 ansfected HEK cells showed that RGS6 prefers Galpha(o) over Galpha(i) as a substrate for its catalyti

141 In a D(2)-Galpha(i1) versus D(2)-Galpha(o) screening, we retrieved five agonists that are

142 GPCR-G protein coupling preferences, and the Galpha(o) substrate preference of RGS6, shape A(1)R- and

143 gonist activity of apomorphine is biased for Galpha(o) We propose that this newly developed assay cou

144 t of Galpha(i1) but are partial agonists for Galpha(o), that the agonist activity of ropinirole is bi

145 ty and that M(2)R signals preferentially via Galpha(o), while A(1)R does not discriminate between inh

146 51 couples to the G-alpha inhibitory protein Galpha(o1) to reduce cyclic adenosine monophosphate (cAM

147 D1Rs are coupled to Galphas/olf, which activate cAMP signaling.

148 rised of one canonical and three extra-large Galpha, one Gbeta and three Ggamma subunits exists.

149 distachyon plants with suppressed levels of Galpha or overexpression of RGS showed significant overl

150 hibit decreased ability to signal via either Galphas or beta-arrestin.

151 rter PEN3, calcium-ATPase ACA8, noncanonical Galpha protein XLG2 and H(+) -ATPases.

152 d as potential candidates to inhibit the RGS/Galpha protein-protein interaction and enhance GPCR sign

153 tor binding sites and terminating at the RGS/Galpha protein-protein interface.

154 ed with OR activation mediated by a specific Galpha protein.

155 des of AC9 regulation include stimulation by Galphas, protein kinase C (PKC) betaII, or calcium-calmo

156 However, Galpha proteins can exist either as monomers or in a com

157 reveal that RgsD can interact with the three Galpha proteins GpaB, GanA, and GpaA, showing the highes

158 tein functional networks are maintained, and Galpha proteins have retained their ability to be deacti

159 t they are subject to the varying endogenous Galpha proteins in a given cell type.

160 However, whether additional Galpha proteins might directly regulate the RH-RhoGEFs w

161 Galpha proteins promote dynamic adjustments of cell shap

162 and physiological interactions of different Galpha proteins with the sole Gbeta remain unexplored.

163 e potent through Galphaz compared with other Galpha proteins.

164 ns and is unique in that it is selective for Galpha (q) Despite only having an RGS domain, responsibl

165 embrane blebbing occurs independently of the Galpha (q/11)- and Galpha (i)-signaling pathways and is

166 ed by Gbetagamma released from Galpha(s) and Galpha(q) Activation of the G(s)-coupled adenosine 2B re

167 In addition, the effects of MRAP2 on the Galpha(q) and beta-arrestin pathways were independent an

168 contrast, obese mutant mice that lacked both Galpha(q) and Galpha(11) selectively in SKM showed sever

169 Mice were created lacking uterine Galpha(q) and Galpha(11); as a result, signaling by all

170 iscuous signaling through both Galpha(s) and Galpha(q) in a dose-dependent manner.

171 ase in cells and find an unexpected role for Galpha(q) in Gbetagamma-dependent activation of phosphol

172 If Galpha(q) is pharmacologically inhibited or genetically

173 We show that pharmacological inhibition of Galpha(q) makes P-REX1 activation by G(q)/G(i)-coupled l

174 This dependence of Gi-Gbetagamma-Ca(2+) on Galpha(q) places an entire signaling branch of G-protein

175 gic receptor stabilize binding of noncognate Galpha(q) protein in its latent cavity, allowing promisc

176 rminus peptides of Galpha(s), Galpha(i), and Galpha(q) proteins assume a small ensemble of unique ori

177 nuclear F-actin assembly via heterotrimeric Galpha(q) proteins.

178 hibited nucleotide exchange on Galpha(s) and Galpha(q) These findings indicate that GBA motifs have v

179 and enables better binding to Galpha(s) and Galpha(q) Unlike the nucleotide-exchange acceleration ob

180 Macrophages lacking both Gnaq (Galpha(q)) and Gna11 (Galpha(11)) or both Gna12 (Galpha(

181 CR, also displays constitutive signaling via Galpha(q), Galpha(i), and Galpha(s) proteins.

182 the G(s) and G(q/11) families (Galpha(s) and Galpha(q), respectively), but not of the G(12/13) family

183 ownstream of Gbetagamma and Galpha(12/13) or Galpha(q), respectively.

184 strated by introduction of this leucine into Galpha(q), resulting in the gain of coupling to GPR35.

185 ude that a coordinated mechanism prioritizes Galpha(q)- and Galpha(13)-mediated signaling to Rho over

186 cells in culture and inhibited the growth of Galpha(q)-driven UM mouse xenografts in vivo.

187 entirely dependent on the presence of active Galpha(q).

188 GTPase-deficient Galpha(q)QL and Galpha(13)QL variants formed stable comp

189 This pathway was inhibited by Galpha(q)QL and Galpha(13)QL, which also prevented CXCR4

190 could be taken to blunt the signaling of non-Galpha(q/11) G proteins.

191 as Lats1/2-deficient cancer cells as well as Galpha(q/11) mutated uveal melanoma.

192 R) directly interacted with GTPase-deficient Galpha(q/11) proteins and preferentially inhibited mitog

193 n endothelial H(+) receptor, and endothelial Galpha(q/11) proteins mediate the CO(2)/H(+) effect on c

194 hich encode alpha subunits of heterotrimeric Galpha(q/11) proteins, occur in about 85% of cases of uv

195 iven by activating mutations at codon 209 in Galpha(q/11) proteins, we envision that similar approach

196 Uterine Galpha(q/11) signaling, in a progesterone-dependent mann

197 e of Trio (TrioC) transfers signals from the Galpha(q/11) subfamily of heterotrimeric G proteins to t

198 ndent but G protein (Galpha(i), Galpha(s) or Galpha(q/11))-independent manner.

199 nal-regulated kinases 1 and 2 by Gbetagamma, Galpha(q/11), and Galpha(i/o)-independent mechanisms.

200 KF-NH(2), and we monitored activation of the Galpha(q/11)-coupled calcium-signaling pathway, beta-arr

201 This study examined the importance of the Galpha(q/11)-coupled class of GPCRs as regulators of ute

202 osine triphosphatase (GTPase) RhoA, enabling Galpha(q/11)-coupled G protein-coupled receptors (GPCRs)

203 models is dependent on co-activation of the Galpha(q/11)-coupled mGlu(1) subtype of metabotropic glu

204 a(11); as a result, signaling by all uterine Galpha(q/11)-coupled receptors was disrupted.

205 may represent cancer drivers operating in a Galpha(q/11)-independent manner.

206 ndocannabinoid release through activation of Galpha(q/11)-type G proteins whereas M(4) transduction o

207 The data reveal rules governing RGS-Galpha recognition, the structural basis of its selectiv

208 the principles governing the selectivity of Galpha regulation by RGS, we examine the catalytic activ

209 hway was stimulated by constitutively active Galpha(s) (Galpha(s)Q227L), which enabled endogenous PRG

210 of Rho GTPases extends our understanding of Galpha(s) activity and establishes RhoGEF coupling as a

211 tion allows increased functional coupling of Galpha(s) and adenylyl cyclase to increase intracellular

212 e also inhibited by Gbetagamma released from Galpha(s) and Galpha(q) Activation of the G(s)-coupled a

213 allowing promiscuous signaling through both Galpha(s) and Galpha(q) in a dose-dependent manner.

214 a(i), DAPLE inhibited nucleotide exchange on Galpha(s) and Galpha(q) These findings indicate that GBA

215 om that in GIV and enables better binding to Galpha(s) and Galpha(q) Unlike the nucleotide-exchange a

216 to members of the G(s) and G(q/11) families (Galpha(s) and Galpha(q), respectively), but not of the G

217 the GBA motif of GIV promotes its binding to Galpha(s) and inhibits nucleotide exchange.

218 ogether, our results demonstrate that active Galpha(s) can recognize PRG as a novel effector directin

219 essant treatment decreased the proportion of Galpha(s) complexed with tubulin.

220 0 uM ketamine for 15 min, which translocated Galpha(s) from lipid raft domains to non-raft domains.

221 Other NMDA antagonist did not translocate Galpha(s) from lipid raft to non-raft domains.

222 They also suggest that the translocation of Galpha(s) from lipid rafts is a reliable hallmark of ant

223 hypothesized that ketamine would translocate Galpha(s) from lipid rafts to non-raft microdomains, sim

224 rom depressed suicide brain showed increased Galpha(s) in lipid-raft domains compared with normal sub

225 depression and the increased localization of Galpha(s) in lipid-raft domains responsible for attenuat

226 state, permitting increased sequestration of Galpha(s) in lipid-raft domains, where it is less likely

227 Active Galpha(s) interacted with isolated PRG DH and PH domains

228 upled receptors, are mutually exclusive with Galpha(s) oncogenic activating mutations, both of which

229 n a CCR2-dependent but G protein (Galpha(i), Galpha(s) or Galpha(q/11))-independent manner.

230 The ketamine-induced Galpha(s) plasma membrane redistribution allows increase

231 tive signaling via Galpha(q), Galpha(i), and Galpha(s) proteins.

232 2R,6R)-hydroxynorketamine (HNK) also induced Galpha(s) redistribution and increased cAMP.

233 This first demonstration that the Galpha(s) subfamily regulates activity of Rho GTPases ex

234 itro study demonstrated that tubulin anchors Galpha(s) to lipid rafts and that increased tubulin acet

235 model predicts that cross-talk between GIV, Galpha(s), and Galpha(i) proteins dampens ligand-stimula

236 Our data show C terminus peptides of Galpha(s), Galpha(i), and Galpha(q) proteins assume a sm

237 eading to reduced efficacy of the G protein, Galpha(s), in depression.

238 Furthermore, tubulin interacts closely with Galpha(s), the G-protein responsible for activation of a

239 Galpha(s), when ensconced in lipid rafts, couples less e

240 ant intrinsic activity for the activation of Galpha(s), while they only show weak or even no beta-arr

241 blocked by a construct derived from the PRG:Galpha(s)-binding region, PRG-linker.

242 The dopamine D5 receptor (D5R) is a Galpha(s)-coupled dopamine receptor belonging to the dop

243 tutively high ciliary cAMP maintained by the Galpha(s)-coupled GPCR, GPR161.

244 Galpha(s)-coupled GPCRs (e.g., the 5-HT(6) serotonin and

245 However, cilia also sequester many other Galpha(s)-coupled GPCRs with unknown potential to regula

246 hologies associated with increased levels of Galpha(s)-coupled receptor agonists (e.g., tumor growth,

247 Galpha(s)-coupled receptor agonists are known to have im

248 ligand of beta(2)-integrins-we show that the Galpha(s)-coupled receptor agonists isoproterenol, epine

249 sleep, a natural condition of low levels of Galpha(s)-coupled receptor agonists, up-regulates integr

250 n recruitment to MC4R, rather than canonical Galpha(s)-mediated cyclic adenosine-monophosphate produc

251 Together, these data identify TAAR1/Galpha(s)-mediated signaling pathways that promote insul

252 We discovered that TAAR1 is coupled to Galpha(s)-signaling pathways in insulin-secreting beta-c

253 l of Arg38 in the N-terminal alphaN-helix of Galpha(s).

254 (CALCRL) to promote egress by activating the Galpha(s)/adenylyl cyclase/cAMP pathway.

255 In addition, this construct interfered with Galpha(s)Q227L's ability to guide PRG's interaction with

256 imulated by constitutively active Galpha(s) (Galpha(s)Q227L), which enabled endogenous PRG to gain af

257 The study also explores the evolution of RGS-Galpha selectivity through ancestral reconstruction and

258 ith selectivity determinants residing in the Galpha sequence.

259 rom the microenvironment, and heterotrimeric Galpha signaling links these receptors to downstream eff

260 Inhibition of different Galpha signaling pathways in cell lines and in vivo usin

261 and their selectivity for a complete set of Galpha substrates using real-time kinetic measurements i

262 For each receptor, we probed chimeric Galpha subunit activation via a transforming growth fact

263 ractions between 148 GPCRs and all 11 unique Galpha subunit C termini.

264 OR pharmacology varies based on the specific Galpha subunit coupled to the KOR.

265 In contrast, the Galpha subunit distinctly affected both the efficacy and

266 s were equally efficacious regardless of the Galpha subunit present, the concentration-response curve

267 dopsis (Col) and in mutants of the canonical Galpha subunit, GPA1, showed inhibition of stomatal open

268 nsight by allowing the direct observation of Galpha subunit-specific effects on opioid pharmacology.

269 ing, and of Gbeta as scaffold for recruiting Galpha subunits and G protein-receptor kinases.

270 Specifically, RGS proteins bind to activated Galpha subunits in G-proteins, accelerate the GTP hydrol

271 paper focuses on how the various inhibitory Galpha subunits influence the pharmacology of full and p

272 These Galpha subunits might in turn favor Rho pathways by prev

273 hat naturally occurring hotspot mutations in Galpha subunits of any of the four families of heterotri

274 ein-modulating effect, i.e. they can bind to Galpha subunits of different classes and either stimulat

275 G(12/13) Artificial mutations that activate Galpha subunits of each of these families have long been

276 ily act as GTPase accelerators for activated Galpha subunits of G-protein coupled receptors, but they

277 y reported to modulate G proteins by binding Galpha subunits of the G(i/o) family (Galpha(i)) over ot

278 ma dimer or loss of the full set of atypical Galpha subunits strongly attenuates an NAE-18:3-induced

279 hough much is known about the specificity of Galpha subunits, the specificity of Gbetagammas activate

280 or, is directly controlled by Rho-activating Galpha subunits.

281 as an effector mechanism shared by the major Galpha subunits.

282 sequence and functional similarity of their Galpha subunits: G(s), G(i/o), G(q/11), and G(12/13) Art

283 apture three distinct conformers showing the Galpha(T) helical domain (alphaHD) contacting the Gbetag

284 yzing GDP-GTP exchange on its alpha subunit (Galpha(T)).

285 EM) structure of PDE6 complexed to GTP-bound Galpha(T).

286 namic nature of the contacts between the two Galpha(T).GTP subunits and PDE6 that supports an alterna

287 The structure reveals two Galpha(T).GTP subunits engaging the PDE6 hetero-tetramer

288 d of the GTP-bound transducin alpha subunit (Galpha(T).GTP) and the cyclic GMP (cGMP) phosphodiestera

289 smaller interface may enable the Ric8A-bound Galpha to interact with GTP.

290 ERK1/2 activation involves both arrestin and Galphas, while Src activation depends solely on arrestin

291 udies show that AC9 is directly regulated by Galphas with weak conditional activation by forskolin; o

292 Galpha(z) is coupled to the prostaglandin EP3 receptor i

293 iptomics analyses reveal islets from HFD-fed Galpha(z) KO mice have a dramatically altered gene expre

294 WT controls, which, along with no impact of Galpha(z) loss or HFD feeding on beta-cell proliferation

295 The inhibitory G protein alpha-subunit (Galpha(z)) is an important modulator of beta-cell functi

296 Full-body Galpha(z)-null mice are protected from hyperglycemia and

297 The protection of Galpha(z)-null mice from HFD-induced diabetes is beta-ce

298 se of islets from HFD-fed beta cell-specific Galpha(z)-null mice is significantly improved as compare

299 beta-cell autonomous, as beta cell-specific Galpha(z)-null mice phenocopy the full-body KOs.

300 being dependent on the presence of beta-cell Galpha(z).