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 Gα_q-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 Gα_i/o or Gα_q/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 Gα_i/Gα_o, the Gα_q/11, and/or the Gα_12/13 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 α_s, two α_i2, two α_o 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 Gα_s by inhibiting its intrinsic GTPase activity. Pertussis toxin (PTX, produced by Bordetella pertussis) irreversibly inactivates most members of the Gα_i 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 Gα_q and Gα₁₁ proteins, since it stimulates inositol phosphate formation in a strictly Gα_q-dependent manner. It should be noted however that PMT stimulates a variety of additional cellular signaling events, which are independent of Gα_q 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 Gα_q/11 proteins. YM-254890 blocks the exchange of GDP for GTP on Gα_q/11 but not on Gα_i 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.

	Gαs	Gαi/o
Family Members and Structural Informationa	Gαs(S)b: 380 aa Gαs(L)b: 394 aa Gαs(XL): 485 aa Gαolf: 380 aa	Gαo(1): 354 aa Gαo(2): 354 aa Gαi1-i3: 354 aa Gαz: 381 aa Gαt1/2: 350 aa Gαgust: 353 aa
Effectors and Effect	Gαs(S)b: adenylyl cyclases ↑ , MaxiK channel ↑ , Src tyrosine kinases (c-Src, Hck) ↑ , GTPase of tubulin ↑ Gαs(XL): adenylyl cyclases ↑ Gαolf: adenylyl cyclase ↑	Gαi: adenylyl cyclase ↓, Rap1GAPII-dependent ERK/MAPkinase activation ↑ , Ca2+ channels ↓ , K+ channels ↑ , GTPase of tubulin ↑ , Src tyrosine kinases (c-Src, Hck) ↑ Gαo: adenylyl cyclases ↓ , Ca2+channels ↓, K+ channels ↑ Gαz: adenylyl cyclases ↓ , Ca2+ channels ↓ , K+ channels ↑ , Rap1GAP GRIN1-mediated activation of Cdc42 ↑ (Gαi,o,z) Gαt: cGMP-PDE ↑
Expression	Gαs: ubiquituous Gαolf: olfactory epithelium, certain CNS Ganglia	Gαo(1/2)b: neurons, neuroendocrine cells, astroglia, heart Gαi1-i3: neurons and many others Gαz: platelets, neurons, adrenal chromaffin cells, neurosecretory cells Gαt1: rod outer segments, taste buds Gαt2: cone outer segments Gαgust: sweet and/or bitter taste buds, chemoreceptor cells in the airways
Pharmacological Modulation (toxin site of action)	Gαs: CTX (Arg201) (C8052) Gαolf: CTX (Arg188)	Gαo(1/2)b: PTX (Cys351) (P7208) Gαi1-i3: PTX (Cys351) Gαz: Not found Gαt1/2: PTX (Cys347) CTX (Arg174) (C8052) Gαgust: PTX (Cys350)
Disease Relevance	Gαs(XL): brachydactyly, trauma-related bleeding tendency, neurological problems Gαs: McCune-Albright syndrome, pseudohypoparathyroidism type Ia/b, testotoxicosis, adenomas of pituitary and thyroid, cholera	Gαi: pertussis, adrenal and ovarian adenomas Gαt: congenital cone dysfunction, night blindness

	Gαq/11	Gα12/13	βγ dimers
Family Members and Structural Informationa	Gαq: 359 aa Gα11: 359 aa Gα14: 359 aa Gα15: 359 aa Gα16: 359 aa	Gα12: 359 aa Gα13: 359 aa	β1-5: 340-353 aa γ1-13: 68-75 aa
Effectors and Effect	Phospholipase Cb isoforms ↑ p63-RhoGEF ↑ (Gαq/11) Bruton's tyrosine kinase ↑ (Gαq) K+ channels (Gαq)	Phospholipase D ↑ Phospholipase Cε ↑ NHE-1 ↑ NOS ↑ E-cadherin-mediated cell adhesion ↑ p115RhoGEF ↑ PDZ-RhoGEF ↑ Leukaemia -associated RhoGEF (LARG) ↑ Radixin ↑ Protein phosphatase 5 ↑ AKAP110-mediated activation of PKA ↑ HSP90 ↑	PLCβs ↑ Adenylyl cyclase I ↓ Adenylyl cyclases II, IV, VII ↑ PI 3 kinasesc ↑ K+ channels (GIRK1,2,4) ↑ Ca2+(N-, P/Q-, R-type) channels ↓ P-Rex1 (guanine nucleotide exchange factor for the small GTPase Rac) ↑ c-Jun N-terminal kinase (JNK) ↑ Src kinases ↑ Tubulin GTPase activity ↑ G protein-coupled receptor kinase recruitment to membrane ↑ Protein kinase D ↑ Brutonâ s tyrosine kinase ↑ p114-RhoGEF ↑
Expression	Gαq/11: ubiquitous Gα15/16: hematopoetic cells	Ubiquitous	β1γ1: retinal rod cells β3γ8: retinal cone cells β5: neurons and neuroendocrine orgαns β5(L): retina but most cell types express multiple β and γ subtypes
Pharmacological Modulation (toxin site of action)	Gαq/11: YM-254890 Gαq: PMT (P5806) Gα14: Not found Gα15: Not found Gα16: Not found	Gα12: Not found Gα13: Not found	βγ dimers: Not found
Disease Relevance	Gαq/11: dermal hyperpigmentation	Not Known	Gβ3: atherosclerosis, essential hypertension, metabolic syndrome

Footnotes:

a) Gα subunit nomenclature: Gα_s and Gα_i are so named for stimulation and inhibition, respectively of adenylyl cyclases: for Gα_o is so named for other, identified as a PTX-sensitive non G_i protein with unknown function.

b)Two splice variants of Gα genes.

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

Abbreviations:

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

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