G-protein Signaling: Back to the Future

Overview

Journal Cell Mol Life Sci

Publisher Springer

Specialty Biology

Date 2005 Mar 5

PMID 15747061

Citations 204

Authors

C R McCudden

M D Hains

R J Kimple

D P Siderovski

F S Willard

Affiliations

Soon will be listed here.

Abstract

Heterotrimeric G-proteins are intracellular partners of G-protein-coupled receptors (GPCRs). GPCRs act on inactive Galpha.GDP/Gbetagamma heterotrimers to promote GDP release and GTP binding, resulting in liberation of Galpha from Gbetagamma. Galpha.GTP and Gbetagamma target effectors including adenylyl cyclases, phospholipases and ion channels. Signaling is terminated by intrinsic GTPase activity of Galpha and heterotrimer reformation - a cycle accelerated by 'regulators of G-protein signaling' (RGS proteins). Recent studies have identified several unconventional G-protein signaling pathways that diverge from this standard model. Whereas phospholipase C (PLC) beta is activated by Galpha(q) and Gbetagamma, novel PLC isoforms are regulated by both heterotrimeric and Ras-superfamily G-proteins. An Arabidopsis protein has been discovered containing both GPCR and RGS domains within the same protein. Most surprisingly, a receptor-independent Galpha nucleotide cycle that regulates cell division has been delineated in both Caenorhabditis elegans and Drosophila melanogaster. Here, we revisit classical heterotrimeric G-protein signaling and explore these new, non-canonical G-protein signaling pathways.

Citing Articles

Mutual coupling of neurons in the circadian master clock: What we can learn from fruit flies.

Helfrich-Forster C, Reinhard N Neurobiol Sleep Circadian Rhythms. 2025; 18:100112.

PMID: 39906412 PMC: 11791320. DOI: 10.1016/j.nbscr.2025.100112.

AGS3-based optogenetic GDI induces GPCR-independent Gβγ signalling and macrophage migration.

Thotamune W, Ubeysinghe S, Rajarathna C, Kankanamge D, Olupothage K, Chandu A Open Biol. 2025; 15(2):240181.

PMID: 39904370 PMC: 11793977. DOI: 10.1098/rsob.240181.

Cannabinoids: Role in Neurological Diseases and Psychiatric Disorders.

Kumar U Int J Mol Sci. 2025; 26(1.

PMID: 39796008 PMC: 11720483. DOI: 10.3390/ijms26010152.

GPCR-like Protein ZmCOLD1 Regulate Plant Height in an ABA Manner.

Zhang X, Zhang Z, Peng H, Wang Z, Li H, Duan Y Int J Mol Sci. 2024; 25(21).

PMID: 39519308 PMC: 11546568. DOI: 10.3390/ijms252111755.

Exploration on cold adaptation of Antarctic lichen via detection of positive selection genes.

Wang Y, Zhang Y, Li R, Qian B, Du X, Qiu X IMA Fungus. 2024; 15(1):29.

PMID: 39252145 PMC: 11386357. DOI: 10.1186/s43008-024-00160-x.

References

Frise E, Knoblich J, Jan L, Jan Y . The Drosophila Numb protein inhibits signaling of the Notch receptor during cell-cell interaction in sensory organ lineage. Proc Natl Acad Sci U S A. 1996; 93(21):11925-32. PMC: 38160. DOI: 10.1073/pnas.93.21.11925. View

Chen C, Manning D . Regulation of G proteins by covalent modification. Oncogene. 2001; 20(13):1643-52. DOI: 10.1038/sj.onc.1204185. View

Kammermeier P, Ruiz-Velasco V, Ikeda S . A voltage-independent calcium current inhibitory pathway activated by muscarinic agonists in rat sympathetic neurons requires both Galpha q/11 and Gbeta gamma. J Neurosci. 2000; 20(15):5623-9. PMC: 6772546. View

Wing M, Houston D, KELLEY G, Der C, Siderovski D, Harden T . Activation of phospholipase C-epsilon by heterotrimeric G protein betagamma-subunits. J Biol Chem. 2001; 276(51):48257-61. DOI: 10.1074/jbc.C100574200. View

Traut T . The functions and consensus motifs of nine types of peptide segments that form different types of nucleotide-binding sites. Eur J Biochem. 1994; 222(1):9-19. DOI: 10.1111/j.1432-1033.1994.tb18835.x. View

Snow B, Betts L, Mangion J, Sondek J, Siderovski D . Fidelity of G protein beta-subunit association by the G protein gamma-subunit-like domains of RGS6, RGS7, and RGS11. Proc Natl Acad Sci U S A. 1999; 96(11):6489-94. PMC: 26909. DOI: 10.1073/pnas.96.11.6489. View

Gotta M, Abraham M, Ahringer J . CDC-42 controls early cell polarity and spindle orientation in C. elegans. Curr Biol. 2001; 11(7):482-8. DOI: 10.1016/s0960-9822(01)00142-7. View

Fukuhara S, Chikumi H, Gutkind J . RGS-containing RhoGEFs: the missing link between transforming G proteins and Rho?. Oncogene. 2001; 20(13):1661-8. DOI: 10.1038/sj.onc.1204182. View

Kohout T, Lefkowitz R . Regulation of G protein-coupled receptor kinases and arrestins during receptor desensitization. Mol Pharmacol. 2002; 63(1):9-18. DOI: 10.1124/mol.63.1.9. View

10.

Grishina G, Berlot C . Mutations at the domain interface of GSalpha impair receptor-mediated activation by altering receptor and guanine nucleotide binding. J Biol Chem. 1998; 273(24):15053-60. DOI: 10.1074/jbc.273.24.15053. View

11.

Berthet J, RALL T, SUTHERLAND E . The relationship of epinephrine and glucagon to liver phosphorylase. IV. Effect of epinephrine and glucagon on the reactivation of phosphorylase in liver homogenates. J Biol Chem. 1957; 224(1):463-75. View

12.

Natochin M, Gasimov K, Artemyev N . Inhibition of GDP/GTP exchange on G alpha subunits by proteins containing G-protein regulatory motifs. Biochemistry. 2001; 40(17):5322-8. DOI: 10.1021/bi015505w. View

13.

Makino E, Handy J, Li T, Arshavsky V . The GTPase activating factor for transducin in rod photoreceptors is the complex between RGS9 and type 5 G protein beta subunit. Proc Natl Acad Sci U S A. 1999; 96(5):1947-52. PMC: 26717. DOI: 10.1073/pnas.96.5.1947. View

14.

Wise A, Jupe S, Rees S . The identification of ligands at orphan G-protein coupled receptors. Annu Rev Pharmacol Toxicol. 2004; 44:43-66. DOI: 10.1146/annurev.pharmtox.44.101802.121419. View

15.

Martin-McCaffrey L, Willard F, Oliveira-dos-Santos A, Natale D, Snow B, Kimple R . RGS14 is a mitotic spindle protein essential from the first division of the mammalian zygote. Dev Cell. 2004; 7(5):763-9. DOI: 10.1016/j.devcel.2004.10.004. View

16.

Qian X, Goderie S, Shen Q, Stern J, Temple S . Intrinsic programs of patterned cell lineages in isolated vertebrate CNS ventricular zone cells. Development. 1998; 125(16):3143-52. DOI: 10.1242/dev.125.16.3143. View

17.

Inanobe A, Morishige K, Takahashi N, Ito H, Yamada M, Takumi T . G beta gamma directly binds to the carboxyl terminus of the G protein-gated muscarinic K+ channel, GIRK1. Biochem Biophys Res Commun. 1995; 212(3):1022-8. DOI: 10.1006/bbrc.1995.2072. View

18.

Lishko P, Martemyanov K, Hopp J, Arshavsky V . Specific binding of RGS9-Gbeta 5L to protein anchor in photoreceptor membranes greatly enhances its catalytic activity. J Biol Chem. 2002; 277(27):24376-81. DOI: 10.1074/jbc.M203237200. View

19.

Gonczy P . Mechanisms of spindle positioning: focus on flies and worms. Trends Cell Biol. 2002; 12(7):332-9. DOI: 10.1016/s0962-8924(02)02306-1. View

20.

Tabuse Y, Izumi Y, Piano F, Kemphues K, Miwa J, Ohno S . Atypical protein kinase C cooperates with PAR-3 to establish embryonic polarity in Caenorhabditis elegans. Development. 1998; 125(18):3607-14. DOI: 10.1242/dev.125.18.3607. View