HomeEnzyme Activity AssaysG Proteins (Heterotrimeric)

G Proteins (Heterotrimeric)

Heterotrimeric G proteins, comprising α, β and γ subunits, respond to extracellular signals generated by activated seven-transmembrane (7TM) receptors by modulating intracellular effector proteins such as enzymes and ion channels. In the inactive state, GDP is tightly bound to the a subunit of the heterotrimer. Upon receptor activation GDP is exchanged for GTP, followed by α-subunit dissociation from βγ or alternatively their molecular rearrangement to form active αGTP and βγ complexes. Both αGTP and βγ dimers are capable of regulating downstream effector functions.

The duration of the signal is determined by the intrinsic GTP hydrolysis rate of the a subunit followed by reassociation of αGDP with βγ. In this way, the heterotrimer is prepared for another round of the activation/deactivation cycle. In addition to the intrinsic GTPase activity of the α subunit, G protein deactivation is accelerated by GTPase activating proteins (GAPs). GAPs for heterotrimeric G proteins include G protein effectors, such as the Gαq-dependent phospholipase Cβ and the Gα13-dependent p115RhoGEF, as well as the family of regulators of G protein signaling (RGS proteins). RGS proteins display GAP activity towards either Gαi/o or Gαq/11 type G proteins, thereby shortening the duration that Gα is GTP bound and βγ is free.

A single ligand occupied receptor is able to activate several G protein molecules during the lifetime of a single αGTP complex. The signal imparted by the binding of a single agonist to its receptor is thus transduced and amplified leading to generation of several active αGTP and βγ molecules during the lifetime of the first αGTP. The diversification of the receptor signal comes about from: i) a single receptor has the ability to affect a group of G proteins, such as the Gαi/Gαo, the Gαq/11, and/or the Gα12/13 class; ii) phosphorylation by kinases of receptors may switch their coupling from one G protein class to another and thus allow coupling to additional sets of effector proteins; iii) α and βγ subunits may have different effects in different cells due to expression of different effectors; iv) G proteins and their effectors can be spatially segregated in a given cell, and; v) effector specificity of βγ complexes is not exclusively determined by the nature of the βγ subunit combination, but depends on the nature of Gα from which βγ is released.

α Subunits are encoded in 15 genes and several transcripts are alternatively spliced (five αs, two αi2, two αo forms). Receptors may discriminate between splice variants, and splice variants may differ in their ability to regulate effector functions. All α subunits appear to be palmitoylated near the N-terminus. Palmitate turns over and may affect regulation of GTPase activity by GAPs of Gα subunits as well their subcellular localization.

βγ Dimers are heterogeneous and encoded in five β and thirteen γ genes. Although some dimers do not form, e.g. β1γ3, β2γ1, and β3γ1, most β and γ subtypes are able to form distinct βγ dimers. Structurally, β subunits are seven-blade propellers, each blade formed of a WD40 motif. γ subunits vary from 68 to 75 amino acids and constitute the most heterogeneous of the three subunit families. All γ subunits are polyisoprenylated at their C-termini. Although a few reports exist showing that a given receptor may require a specific β or γ subunit within the heterotrimer for effector stimulation, it is not known which αβγ combinations exist in vivo, likewise the factors governing their selective assembly are also not known. Although in vitro most a subunits can associate with most βγ dimers, specificity of in vivo; αβγ dimer assembly may be controlled by cell-type specific or temporal regulation of expression.

Pharmacological agonists and antagonists are used to define Gα protein function. They include both the hydrolysis resistant GTP analogs, GTP-γ-S and GDP-β-S, that hold the Gα subunit in active and inactive conformations, respectively, and various bacterial toxins. Cholera toxin (CTX, produced by Vibrio cholerae) is responsible for the infectious gastro-enteritis known as cholera. CTX irreversibly activates Gαs by inhibiting its intrinsic GTPase activity. Pertussis toxin (PTX, produced by Bordetella pertussis) irreversibly inactivates most members of the Gαi family by uncoupling them from their cognate receptors. PTX is responsible for the highly contagious respiratory tract infection known as whooping cough. Pasteurella multocida toxin (PMT, produced by Pasteurella multocida) offers the possibility to discriminate between Gαq and Gα11 proteins, since it stimulates inositol phosphate formation in a strictly Gαq-dependent manner. It should be noted however that PMT stimulates a variety of additional cellular signaling events, which are independent of Gαq protein function, thus limiting its use to dissect cellular signaling pathways. Recently, YM-254890 has been described as a novel, specific, and cell permeable inhibitor of Gαq/11 proteins. YM-254890 blocks the exchange of GDP for GTP on Gαq/11 but not on Gαi or Gα15 subunits. It is a cyclic depsipeptide isolated from the culture broth of Chromobacterium sp. QS3666.

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.


a) Gα subunit nomenclature: Gαs and Gαi are so named for stimulation and inhibition, respectively of adenylyl cyclases: for Gαo is so named for other, identified as a PTX-sensitive non Gprotein with unknown function.

b)Two splice variants of Gα genes.

c) Blocked by wortmannin (W1628) and LY-294002 (L9908).


CTX: Cholera toxin
PMT: Pasteurella multocida toxin
PTX: Pertussis toxin

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Adams DJ, Callaghan B, Berecki G. 2012. Analgesic conotoxins: block and G protein-coupled receptor modulation of N-type (CaV2.2) calcium channels. 166(2):486-500.
Birnbaumer L, Birnbaumer M. G Proteins in Signal Transduction.153-252.
Blad CC, Tang C, Offermanns S. 2012. G protein-coupled receptors for energy metabolites as new therapeutic targets. Nat Rev Drug Discov. 11(8):603-619.
Bunemann M, Frank M, Lohse MJ. 2003. Gi protein activation in intact cells involves subunit rearrangement rather than dissociation. Proceedings of the National Academy of Sciences. 100(26):16077-16082.
Cabrera-Vera TM, Vanhauwe J, Thomas TO, Medkova M, Preininger A, Mazzoni MR, Hamm HE. 2003. Insights into G Protein Structure, Function, and Regulation. Endocrine Reviews. 24(6):765-781.
Clapham DE, Neer EJ. 1997. G PROTEIN ?? SUBUNITS. Annu. Rev. Pharmacol. Toxicol.. 37(1):167-203.
Farfel Z, Bourne HR, Iiri T. 1999. The Expanding Spectrum of G Protein Diseases. N Engl J Med. 340(13):1012-1020.
Hart MJ. 1998. Direct Stimulation of the Guanine Nucleotide Exchange Activity of p115 RhoGEF by G13. 280(5372):2112-2114.
Hepler JR, Gilman AG. 1992. G proteins. Trends in Biochemical Sciences. 17(10):383-387.
Huang C, Tesmer JJG. 2011. Recognition in the Face of Diversity: Interactions of Heterotrimeric G proteins and G Protein-coupled Receptor (GPCR) Kinases with Activated GPCRs. J. Biol. Chem.. 286(10):7715-7721.
Kleuss C. 2003. Galphas is palmitoylated at the N-terminal glycine. 22(4):826-832.
Kostenis E. 2001. Is G?16 the optimal tool for fishing ligands of orphan G-protein-coupled receptors?. Trends in Pharmacological Sciences. 22(11):560-564.
Milligan G, Parenti M, Magee AI. 1995. The dynamic role of palmitoylation in signal transduction. Trends in Biochemical Sciences. 20(5):181-186.
O'Callaghan K, Kuliopulos A, Covic L. 2012. Turning Receptors On and Off with Intracellular Pepducins: New Insights into G-protein-coupled Receptor Drug Development. J. Biol. Chem.. 287(16):12787-12796.
Rojas A, Dingledine R. 2013. Ionotropic Glutamate Receptors: Regulation by G-Protein-Coupled Receptors. Mol Pharmacol. 83(4):746-752.
Ross EM, Wilkie TM. 2000. GTPase-Activating Proteins for Heterotrimeric G Proteins: Regulators of G Protein Signaling (RGS) and RGS-Like Proteins. Annu. Rev. Biochem.. 69(1):795-827.
Siffert W. 2005. G Protein Polymorphisms in Hypertension, Atherosclerosis, and Diabetes. Annu. Rev. Med.. 56(1):17-28.
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