gtp binding protein gamma subunits


Summary: Heterotrimeric GTP-binding protein subunits that tightly associate with GTP-BINDING PROTEIN BETA SUBUNITS. A dimer of beta and gamma subunits is formed when the GTP-BINDING PROTEIN ALPHA SUBUNIT dissociates from the GTP-binding protein heterotrimeric complex. The beta-gamma dimer can play an important role in signal transduction by interacting with a variety of second messengers.

Top Publications

  1. Auer Grumbach M, Schlotter Weigel B, Lochmuller H, Strobl Wildemann G, Auer Grumbach P, Fischer R, et al. Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. Ann Neurol. 2005;57:415-24 pubmed
    ..Sensory nerve conduction studies were rarely pathological. Our study indicates that the dominant N88S mutation in the Berardinelli-Seip congenital lipodystrophy gene 2 leads to a broad spectrum of motor neuron disorders. ..
  2. Murray D, McLaughlin S, Honig B. The role of electrostatic interactions in the regulation of the membrane association of G protein beta gamma heterodimers. J Biol Chem. 2001;276:45153-9 pubmed
    ..Sequence analysis and homology model building suggest that our conclusions may be generalized to other Gbetagamma and phosducin isoforms as well. ..
  3. Agarwal A, Simha V, Oral E, Moran S, Gorden P, O Rahilly S, et al. Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J Clin Endocrinol Metab. 2003;88:4840-7 pubmed
    ..We conclude that besides AGPAT2 and BSCL2, there may be additional loci for CGL. The genetic heterogeneity in CGL patients is accompanied by phenotypic heterogeneity. ..
  4. Lundin C, Nordström R, Wagner K, Windpassinger C, Andersson H, von Heijne G, et al. Membrane topology of the human seipin protein. FEBS Lett. 2006;580:2281-4 pubmed
    ..Our results suggest that the predominant form of seipin is 462 residues long and has an N(cyt)-C(cyt) orientation with a long luminal loop between the two transmembrane helices. ..
  5. Krugmann S, Hawkins P, Pryer N, Braselmann S. Characterizing the interactions between the two subunits of the p101/p110gamma phosphoinositide 3-kinase and their role in the activation of this enzyme by G beta gamma subunits. J Biol Chem. 1999;274:17152-8 pubmed
    ..While modifications of the N terminus of p110gamma could modulate its intrinsic catalytic activity, binding to the N-terminal region of p101 was found to be indispensable for activation of heterodimers with Gbetagamma. ..
  6. Evanko D, Thiyagarajan M, Siderovski D, Wedegaertner P. Gbeta gamma isoforms selectively rescue plasma membrane localization and palmitoylation of mutant Galphas and Galphaq. J Biol Chem. 2001;276:23945-53 pubmed
  7. Reusch H, Schaefer M, Plum C, Schultz G, Paul M. Gbeta gamma mediate differentiation of vascular smooth muscle cells. J Biol Chem. 2001;276:19540-7 pubmed
    ..We conclude that receptor-mediated differentiation of VSM cells requires Gbetagamma and an intact Ras/Raf/MEK/ERK signaling. ..
  8. Windpassinger C, Auer Grumbach M, Irobi J, Patel H, Petek E, Hörl G, et al. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome. Nat Genet. 2004;36:271-6 pubmed
    ..We show that seipin is an integral membrane protein of the endoplasmic reticulum (ER). The amino acid substitutions N88S and S90L affect glycosylation of seipin and result in aggregate formation leading to neurodegeneration. ..
  9. Irobi J, Van den Bergh P, Merlini L, Verellen C, Van Maldergem L, Dierick I, et al. The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V. Brain. 2004;127:2124-30 pubmed
    ..These observations broaden the clinical phenotype of disorders associated with BSCL2 mutations, having consequences for molecular genetic testing. ..

More Information


  1. Dohlman H, Thorner J. Regulation of G protein-initiated signal transduction in yeast: paradigms and principles. Annu Rev Biochem. 2001;70:703-54 pubmed
  2. Agarwal A, Garg A. Seipin: a mysterious protein. Trends Mol Med. 2004;10:440-4 pubmed
  3. Chen S, Spiegelberg B, Lin F, Dell E, Hamm H. Interaction of Gbetagamma with RACK1 and other WD40 repeat proteins. J Mol Cell Cardiol. 2004;37:399-406 pubmed
    ..Here we will describe the molecular mechanism underlying this interaction and the implications of the interaction on the signal transduction of G-protein and RACK1. ..
  4. Chen S, Dell E, Lin F, Sai J, Hamm H. RACK1 regulates specific functions of Gbetagamma. J Biol Chem. 2004;279:17861-8 pubmed
    ..Similarly, RACK1 does not affect signal transduction through the Galpha subunits of G(i), G(s), or G(q). Collectively, these findings suggest a role of RACK1 in regulating specific functions of Gbetagamma. ..
  5. van de Warrenburg B, Scheffer H, van Eijk J, Versteeg M, Kremer H, Zwarts M, et al. BSCL2 mutations in two Dutch families with overlapping Silver syndrome-distal hereditary motor neuropathy. Neuromuscul Disord. 2006;16:122-5 pubmed
  6. Weitmann S, Schultz G, Kleuss C. Adenylyl cyclase type II domains involved in Gbetagamma stimulation. Biochemistry. 2001;40:10853-8 pubmed
  7. Robishaw J, Berlot C. Translating G protein subunit diversity into functional specificity. Curr Opin Cell Biol. 2004;16:206-9 pubmed
    ..Although much remains to be learned, the assembly of specific alphabetagamma subunit combinations seems to involve both structural and spatial factors. ..
  8. Whiteway M, Thomas D. Site-directed mutations altering the CAAX box of Ste18, the yeast pheromone-response pathway G gamma subunit. Genetics. 1994;137:967-76 pubmed
    ..These results suggest that the C terminus of Ste18 and the Gpa1 protein have overlapping roles in some aspect of yeast G protein function such as membrane targeting. ..
  9. Szymanski K, Binns D, Bartz R, Grishin N, Li W, Agarwal A, et al. The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc Natl Acad Sci U S A. 2007;104:20890-5 pubmed
    ..The genes identified in our screen should be of value in understanding the pathway of lipid droplet biogenesis and maintenance and the cause of some lipodystrophies. ..
  10. Cafforio G, Calabrese R, Morelli N, Mancuso M, Piazza S, Martinuzzi A, et al. The first Italian family with evidence of pyramidal impairment as phenotypic manifestation of Silver syndrome BSCL2 gene mutation. Neurol Sci. 2008;29:189-91 pubmed publisher
    ..This family confirms the clinical heterogeneity associated with this specific mutation. Moreover, this is the first report in which neuroimaging seems to confirm the pyramidal alterations in dHMN associated to SPG17. ..
  11. Leeuw T, Wu C, Schrag J, Whiteway M, Thomas D, Leberer E. Interaction of a G-protein beta-subunit with a conserved sequence in Ste20/PAK family protein kinases. Nature. 1998;391:191-5 pubmed
  12. Niu J, Profirovic J, Pan H, Vaiskunaite R, Voyno Yasenetskaya T. G Protein betagamma subunits stimulate p114RhoGEF, a guanine nucleotide exchange factor for RhoA and Rac1: regulation of cell shape and reactive oxygen species production. Circ Res. 2003;93:848-56 pubmed
    ..The findings help to explain the integrated effects of LPA and other G-protein receptor-coupled agonists on actin stress fiber formation, cell shape change, and ROS production. ..
  13. Whiteway M, Clark K, Leberer E, Dignard D, Thomas D. Genetic identification of residues involved in association of alpha and beta G-protein subunits. Mol Cell Biol. 1994;14:3223-9 pubmed
    ..Because the ability of the modified G alpha subunit to suppress the Ste4 mutations is allele specific, it is likely that the residues defined by this analysis play a direct role in G-protein subunit association. ..
  14. Blackmer T, Larsen E, Takahashi M, Martin T, Alford S, Hamm H. G protein betagamma subunit-mediated presynaptic inhibition: regulation of exocytotic fusion downstream of Ca2+ entry. Science. 2001;292:293-7 pubmed
    ..Thus, Gbetagamma blocked neurotransmitter release downstream of Ca2+ entry and may directly target the exocytotic fusion machinery at the presynaptic terminal. ..
  15. Landry S, Hoffman C. The git5 Gbeta and git11 Ggamma form an atypical Gbetagamma dimer acting in the fission yeast glucose/cAMP pathway. Genetics. 2001;157:1159-68 pubmed
  16. Hirschman J, Jenness D. Dual lipid modification of the yeast ggamma subunit Ste18p determines membrane localization of Gbetagamma. Mol Cell Biol. 1999;19:7705-11 pubmed
    ..We conclude that tight membrane attachment of the wild-type Gbetagamma depends on palmitoylation at Cys 106 and prenylation at Cys 107 of Ste18p. ..
  17. Krugmann S, Cooper M, Williams D, Hawkins P, Stephens L. Mechanism of the regulation of type IB phosphoinositide 3OH-kinase byG-protein betagamma subunits. Biochem J. 2002;362:725-31 pubmed
    ..We conclude that Gbetagammas activate type IB PI3K by a mechanism other than translocation to the plasma membrane. ..
  18. Hirschman J, De Zutter G, Simonds W, Jenness D. The G beta gamma complex of the yeast pheromone response pathway. Subcellular fractionation and protein-protein interactions. J Biol Chem. 1997;272:240-8 pubmed
    ..These results indicate that at least 40% of Ste4p and Ste18p are part of a G betagamma complex at the plasma membrane and that stable association of this complex with the plasma membrane requires the presence of G alpha. ..
  19. Whiteway M, Wu C, Leeuw T, Clark K, Fourest Lieuvin A, Thomas D, et al. Association of the yeast pheromone response G protein beta gamma subunits with the MAP kinase scaffold Ste5p. Science. 1995;269:1572-5 pubmed
    ..Thus, association of the G protein and the MAP kinase cassette via the scaffolding protein Ste5p may transmit the G protein signal. ..
  20. Gotta M, Ahringer J. Distinct roles for Galpha and Gbetagamma in regulating spindle position and orientation in Caenorhabditis elegans embryos. Nat Cell Biol. 2001;3:297-300 pubmed
    ..Gbetagamma is important in regulating migration of the centrosome around the nucleus and hence in orientating the mitotic spindle. Galpha is required for asymmetric spindle positioning in the one-celled embryo. ..
  21. Blackmer T, Larsen E, Bartleson C, Kowalchyk J, Yoon E, Preininger A, et al. G protein betagamma directly regulates SNARE protein fusion machinery for secretory granule exocytosis. Nat Neurosci. 2005;8:421-5 pubmed
    ..Here we show inhibitory coupling between GPCRs and vesicle exocytosis mediated directly by Gbetagamma interactions with the Ca(2+)-dependent fusion machinery. ..
  22. Taurin S, Hogarth K, Sandbo N, Yau D, Dulin N. Gbetagamma-mediated prostacyclin production and cAMP-dependent protein kinase activation by endothelin-1 promotes vascular smooth muscle cell hypertrophy through inhibition of glycogen synthase kinase-3. J Biol Chem. 2007;282:19518-25 pubmed
  23. Jamora C, Yamanouye N, van Lint J, Laudenslager J, Vandenheede J, Faulkner D, et al. Gbetagamma-mediated regulation of Golgi organization is through the direct activation of protein kinase D. Cell. 1999;98:59-68 pubmed
    ..Our findings suggest a possible mechanism by which the direct interaction of Gbetagamma with PKD regulates the dynamics of Golgi membranes and protein secretion. ..
  24. Magre J, Delepine M, Khallouf E, Gedde Dahl T, Van Maldergem L, Sobel E, et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet. 2001;28:365-70 pubmed
    ..These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance. ..
  25. Van Maldergem L, Magre J, Khallouf T, Gedde Dahl T, Delepine M, Trygstad O, et al. Genotype-phenotype relationships in Berardinelli-Seip congenital lipodystrophy. J Med Genet. 2002;39:722-33 pubmed
    ..The higher prevalence of intellectual impairment and the increased risk of premature death in BSCL2 compared to BSCL1 emphasise the importance of molecular diagnosis of this syndrome and have clear implications for genetic counselling. ..
  26. Ito D, Suzuki N. Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases. Ann Neurol. 2007;61:237-50 pubmed
    ..These findings demonstrate that seipin/BSCL2-related motor neuron diseases are novel conformational diseases, and we suspect that they are tightly associated with ER stress-mediated cell death. ..
  27. Ebihara K, Kusakabe T, Masuzaki H, Kobayashi N, Tanaka T, Chusho H, et al. Gene and phenotype analysis of congenital generalized lipodystrophy in Japanese: a novel homozygous nonsense mutation in seipin gene. J Clin Endocrinol Metab. 2004;89:2360-4 pubmed
    ..We did not find any AGPAT2 mutations in our Japanese patients, suggesting that AGPAT2 is a minor causative gene, if any, for CGL in Japanese. This is the first report on gene and phenotype analysis of CGL in Japanese. ..
  28. Hsueh Y, Xue C, Heitman J. G protein signaling governing cell fate decisions involves opposing Galpha subunits in Cryptococcus neoformans. Mol Biol Cell. 2007;18:3237-49 pubmed
    ..The incorporation of an additional Galpha into the regulatory circuit enabled increased signaling complexity and facilitated cell fate decisions involving choice between yeast growth and filamentous asexual/sexual development. ..
  29. Menard R, Mattingly R. Gbetagamma subunits stimulate p21-activated kinase 1 (PAK1) through activation of PI3-kinase and Akt but act independently of Rac1/Cdc42. FEBS Lett. 2004;556:187-92 pubmed
    ..These results reveal that stimulation of PAK1 by Gbetagamma can occur via a PI3-kinase and Akt pathway that does not require Rac1 or Cdc42. ..
  30. Nern A, Arkowitz R. A Cdc24p-Far1p-Gbetagamma protein complex required for yeast orientation during mating. J Cell Biol. 1999;144:1187-202 pubmed
    ..These results suggest that formation of a Cdc24p-Far1p-Gbetagamma complex functions as a landmark for orientation of the cytoskeleton during growth towards an external signal. ..
  31. Cotter E, Von Offenberg Sweeney N, Coen P, Birney Y, Glucksman M, Cahill P, et al. Regulation of endopeptidases EC3.4.24.15 and EC3.4.24.16 in vascular endothelial cells by cyclic strain: role of Gi protein signaling. Arterioscler Thromb Vasc Biol. 2004;24:457-63 pubmed
    ..15 +42%, EP24.16 +56%). Our findings suggest that cyclic strain putatively regulates both the mRNA expression and enzymatic function of EP24.15 and EP24.16 in BAECs via alternate Gi protein signaling pathways. ..
  32. Díaz Añel A. Phospholipase C beta3 is a key component in the Gbetagamma/PKCeta/PKD-mediated regulation of trans-Golgi network to plasma membrane transport. Biochem J. 2007;406:157-65 pubmed
    ..In conclusion, we demonstrate that fission of transport carriers at the TGN is dependent on PI-PLCs, specifically PLCbeta3, which is necessary to activate PKCeta and PKD in that Golgi compartment, via DAG production. ..
  33. Ohta M, Mimori K, Fukuyoshi Y, Kita Y, Motoyama K, Yamashita K, et al. Clinical significance of the reduced expression of G protein gamma 7 (GNG7) in oesophageal cancer. Br J Cancer. 2008;98:410-7 pubmed publisher
    ..GNG7 suppression represents a new prognostic indicator in cases of oesophageal cancer. GNG7 might be suppressed by LOH and promoter hypermethylation or by microRNA. ..
  34. Tu H, Rondard P, Xu C, Bertaso F, Cao F, Zhang X, et al. Dominant role of GABAB2 and Gbetagamma for GABAB receptor-mediated-ERK1/2/CREB pathway in cerebellar neurons. Cell Signal. 2007;19:1996-2002 pubmed
    ..These findings suggest a role of GABA(B) receptor in long-term change in the central nervous system. ..
  35. Jansen G, Weinkove D, Plasterk R. The G-protein gamma subunit gpc-1 of the nematode C.elegans is involved in taste adaptation. EMBO J. 2002;21:986-94 pubmed
    ..Our finding that G proteins, OSM-9 and ADP-1 are involved in taste adaptation offer the first molecular insight into this process. ..
  36. Miranda D, Wajchenberg B, Calsolari M, Aguiar M, Silva J, Ribeiro M, et al. Novel mutations of the BSCL2 and AGPAT2 genes in 10 families with Berardinelli-Seip congenital generalized lipodystrophy syndrome. Clin Endocrinol (Oxf). 2009;71:512-7 pubmed publisher
    ..299G>A). We have demonstrated four novel mutations of the BSCL2 and AGPAT2 genes responsible for Berardinelli-Seip syndrome and Brunzell syndrome (AGPAT2-related syndrome). ..
  37. Sachdev P, Menon S, Kastner D, Chuang J, Yeh T, Conde C, et al. G protein beta gamma subunit interaction with the dynein light-chain component Tctex-1 regulates neurite outgrowth. EMBO J. 2007;26:2621-32 pubmed
  38. Li G, Shi Y, Huang H, Zhang Y, Wu K, Luo J, et al. Internalization of the human nicotinic acid receptor GPR109A is regulated by G(i), GRK2, and arrestin3. J Biol Chem. 2010;285:22605-18 pubmed publisher
  39. Chan A, Wong Y. Gbetagamma signaling and Ca2+ mobilization co-operate synergistically in a Sos and Rac-dependent manner in the activation of JNK by Gq-coupled receptors. Cell Signal. 2004;16:823-36 pubmed
    ..We propose that the co-operative effect between Gbetagamma-mediated signaling and the increased intracellular Ca(2+) level represents a robust mechanism for the stimulation of JNK by G(q)-coupled receptors. ..
  40. Zhang N, Long Y, Devreotes P. Ggamma in dictyostelium: its role in localization of gbetagamma to the membrane is required for chemotaxis in shallow gradients. Mol Biol Cell. 2001;12:3204-13 pubmed
    ..Thus, a full complement of membrane-tethered Gbetagamma is required for sensing shallow gradients, but is not essential for responses to increments in extracellular stimuli. ..
  41. Kinoshita Kawada M, Oberdick J, Xi Zhu M. A Purkinje cell specific GoLoco domain protein, L7/Pcp-2, modulates receptor-mediated inhibition of Cav2.1 Ca2+ channels in a dose-dependent manner. Brain Res Mol Brain Res. 2004;132:73-86 pubmed
    ..This provides a framework for designing further experiments to determine how dendritic local fluctuations in L7 protein levels might influence signal processing in Purkinje cells. ..
  42. Hill J, Peralta E. Inhibition of a Gi-activated potassium channel (GIRK1/4) by the Gq-coupled m1 muscarinic acetylcholine receptor. J Biol Chem. 2001;276:5505-10 pubmed
  43. Ghosh M, Smrcka A. Assay for G protein-dependent activation of phospholipase C beta using purified protein components. Methods Mol Biol. 2004;237:67-75 pubmed
    ..It can also be used to assess the functionality of the components after modification by mutagenesis, chemical modification, or in the presence of competing molecules. ..
  44. Mirshahi T, Jin T, Logothetis D. G beta gamma and KACh: old story, new insights. Sci STKE. 2003;2003:PE32 pubmed
    ..This mechanism of channel gating is conserved among K+ channels from bacteria to mammals and may represent a common mechanism for K+ channel gating. ..
  45. Flynn R, Mahavadi S, Murthy K, Kellum J, Kuemmerle J. Insulin-like growth factor-binding protein-5 stimulates growth of human intestinal muscle cells by activation of G{alpha}i3. Am J Physiol Gastrointest Liver Physiol. 2009;297:G1232-8 pubmed publisher
    ..Our results indicate that endogenous IGFBP-5 activates Gi3 and regulates smooth muscle growth, IGF-I production, and collagen production via the alpha-subunit of Gi3, independently of IGF-I, in normal human intestinal muscle cells. ..
  46. Philip F, Kadamur G, Silos R, Woodson J, Ross E. Synergistic activation of phospholipase C-beta3 by Galpha(q) and Gbetagamma describes a simple two-state coincidence detector. Curr Biol. 2010;20:1327-35 pubmed publisher
    ..Any two-state enzyme is predicted to respond synergistically to multiple activating ligands if, but only if, its basal activity is strongly suppressed. ..
  47. Vogt A, Lutz S, Rümenapp U, Han L, Jakobs K, Schmidt M, et al. Regulator of G-protein signalling 3 redirects prototypical Gi-coupled receptors from Rac1 to RhoA activation. Cell Signal. 2007;19:1229-37 pubmed
    ..Considering the essential roles of Rac1 and RhoA in many signalling pathways, this additional function of RGS3L indicates a specific role of this protein in cellular signalling networks. ..
  48. Wells C, Dingus J, Hildebrandt J. Role of the chaperonin CCT/TRiC complex in G protein betagamma-dimer assembly. J Biol Chem. 2006;281:20221-32 pubmed
    ..We conclude that the chaperonin CCT/TRiC complex binds to and folds Gbeta subunits and that CCT/TRiC mediates Gbetagamma dimer formation by an ATP-dependent reaction. ..
  49. Myung C, Lim W, DeFilippo J, Yasuda H, Neubig R, Garrison J. Regions in the G protein gamma subunit important for interaction with receptors and effectors. Mol Pharmacol. 2006;69:877-87 pubmed
    ..The results indicate that both the N- and C-terminal regions of the gamma subunit impart specificity to receptor and effector interactions. ..
  50. Kino T, Tiulpakov A, Ichijo T, Chheng L, Kozasa T, Chrousos G. G protein beta interacts with the glucocorticoid receptor and suppresses its transcriptional activity in the nucleus. J Cell Biol. 2005;169:885-96 pubmed
    ..We conclude that the Gbetagamma complex interacts with the GR and suppresses its transcriptional activity by associating with the transcriptional complex formed on GR-responsive promoters. ..
  51. Rusinova R, Mirshahi T, Logothetis D. Specificity of Gbetagamma signaling to Kir3 channels depends on the helical domain of pertussis toxin-sensitive Galpha subunits. J Biol Chem. 2007;282:34019-30 pubmed
    ..These results implicate the helical domain of Galpha(i) proteins as a critical determinant of Gbetagamma signaling specificity. ..
  52. Newman Tancredi A, Cussac D, Marini L, Touzard M, Millan M. h5-HT(1B) receptor-mediated constitutive Galphai3-protein activation in stably transfected Chinese hamster ovary cells: an antibody capture assay reveals protean efficacy of 5-HT. Br J Pharmacol. 2003;138:1077-84 pubmed
  53. Hippe H, Wolf N, Abu Taha I, Mehringer R, Just S, Lutz S, et al. The interaction of nucleoside diphosphate kinase B with Gbetagamma dimers controls heterotrimeric G protein function. Proc Natl Acad Sci U S A. 2009;106:16269-74 pubmed publisher
    ..Thus, our results suggest a role for the interaction of NDPK B with Gbetagamma dimers and caveolins in regulating membranous G protein content and maintaining normal G protein function in vivo. ..