Gi alpha subunit

G_i protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the G_i/o (G_i /G_o ) family or G_i/o/z/t family to include closely related family members. G alpha subunits may be referred to as G_i alpha, G_αi, or G_iα.

G protein subunit alpha i1
Identifiers
Symbol	GNAI1
NCBI gene	2770
HGNC	4384
OMIM	139310
PDB	3UMR
RefSeq	NM_002069
UniProt	P63096
Other data
Locus	Chr. 7 q21-q22
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G protein subunit alpha i2
Identifiers
Symbol	GNAI2
NCBI gene	2771
HGNC	4385
OMIM	139360
RefSeq	NM_002070
UniProt	P04899
Other data
Locus	Chr. 3 p21
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G protein subunit alpha i3
Identifiers
Symbol	GNAI3
NCBI gene	2773
HGNC	4387
OMIM	139370
PDB	2ODE
RefSeq	NM_006496
UniProt	P08754
Other data
Locus	Chr. 1 p13
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G protein subunit alpha o1
Identifiers
Symbol	GNAO1
NCBI gene	2775
HGNC	4389
OMIM	139311
RefSeq	NM_020988
UniProt	P09471,
Other data
Locus	Chr. 16 q13
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G protein subunit alpha z
Identifiers
Symbol	GNAZ
NCBI gene	2781
HGNC	4395
OMIM	139160
RefSeq	NM_002073
UniProt	P19086
Other data
Locus	Chr. 22 q11.22-11.23
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G protein subunit alpha t1, Transducin 1 (rod)
Identifiers
Symbol	GNAT1
NCBI gene	2779
HGNC	4393
OMIM	139330
RefSeq	NM_000172
UniProt	P11488
Other data
Locus	Chr. 3 p21.31
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G protein subunit alpha t2, Transducin 2 (cone)
Identifiers
Symbol	GNAT2
NCBI gene	2780
HGNC	4394
OMIM	139340
RefSeq	NM_005272
UniProt	P19087
Other data
Locus	Chr. 1 p13.3
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G protein subunit alpha t3, Gustducin
Identifiers
Symbol	GNAT3
NCBI gene	346562
HGNC	22800
OMIM	139395
RefSeq	NM_001102386
UniProt	A8MTJ3
Other data
Locus	Chr. 7 q21.11
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Family members

There are four distinct subtypes of alpha subunits in the G_i/o/z/t alpha subunit family that define four families of heterotrimeric G proteins:

• G_i proteins: G_i1α, G_i2α, and G_i3α
• G_o protein: G_oα (in mouse there is alternative splicing to generate G_o1α and G_o2α)
• G_z protein: G_zα
• Transducins (G_t proteins): G_t1α, G_t2α, G_t3α

G_iα proteins

G_i1α

G_i1α is encoded by the gene GNAI1.

G_i2α

G_i2α is encoded by the gene GNAI2.

G_i3α

G_i3α is encoded by the gene GNAI3.

G_oα protein

G_o1α is encoded by the gene GNAO1.

G_zα protein

G_zα is encoded by the gene GNAZ.

Transducin proteins

Main article: Transducin

G_t1α

Transducin/G_t1α is encoded by the gene GNAT1.

G_t2α

Transducin 2/G_t2α is encoded by the gene GNAT2.

G_t3α

Main article: Gustducin

Gustducin/G_t3α is encoded by the gene GNAT3.

Function

Main article: Heterotrimeric G protein

The general function of G_i/o/z/t is to activate intracellular signaling pathways in response to activation of cell surface G protein-coupled receptors (GPCRs). GPCRs function as part of a three-component system of receptor-transducer-effector.^[1][2] The transducer in this system is a heterotrimeric G protein, composed of three subunits: a Gα protein such as G_iα, and a complex of two tightly linked proteins called Gβ and Gγ in a Gβγ complex.^[1][2] When not stimulated by a receptor, Gα is bound to GDP and to Gβγ to form the inactive G protein trimer.^[1][2] When the receptor binds an activating ligand outside the cell (such as a hormone or neurotransmitter), the activated receptor acts as a guanine nucleotide exchange factor to promote GDP release from and GTP binding to Gα, which drives dissociation of GTP-bound Gα from Gβγ.^[1][2] GTP-bound Gα and Gβγ are then freed to activate their respective downstream signaling enzymes.

G_i proteins primarily inhibit the cAMP dependent pathway by inhibiting adenylyl cyclase activity, decreasing the production of cAMP from ATP, which, in turn, results in decreased activity of cAMP-dependent protein kinase. Therefore, the ultimate effect of G_i is the inhibition of the cAMP-dependent protein kinase. The Gβγ liberated by activation of G_i and G_o proteins is particularly able to activate downstream signaling to effectors such as G protein-coupled inwardly-rectifying potassium channels (GIRKs).^[3] G_i and G_o proteins are substrates for pertussis toxin, produced by Bordetella pertussis, the infectious agent in whooping cough. Pertussis toxin is an ADP-ribosylase enzyme that adds an ADP-ribose moiety to a particular cysteine residue in G_iα and G_oα proteins, preventing their coupling to and activation by GPCRs, thus turning off G_i and G_o cell signaling pathways.^[4]

G_z proteins also can link GPCRs to inhibition of adenylyl cyclase, but G_z is distinct from G_i/G_o by being insensitive to inhibition by pertussis toxin.^[5]

G_t proteins function in sensory transduction. The Transducins G_t1 and G_t2 serve to transduce signals from G protein-coupled receptors that receive light during vision. Rhodopsin in dim light night vision in retinal rod cells couples to G_t1, and color photopsins in color vision in retinal cone cells couple to G_t2, respectively. G_t3/Gustducin subunits transduce signals in the sense of taste (gustation) in taste buds by coupling to G protein-coupled receptors activated by sweet or bitter substances.

Receptors

The following G protein-coupled receptors couple to G_i/o subunits:

• 5-HT₁ and 5-HT₅ serotonergic receptors
• Acetylcholine M₂ & M₄ receptors
• Adenosine A₁ & A₃ receptors
• Adrenergic α_2A, α_2B, & α_2C receptors
• Apelin receptors
• Calcium-sensing receptor
• Cannabinoid receptors (CB1 and CB2)
• Chemokine CXCR4 receptor
• Dopamine D₂, D₃ and D₄ receptors
• GABA_B receptor
• Glutamate mGluR2, mGluR3, mGluR4, mGluR6, mGluR7, & mGluR8 receptors
• Histamine H₃ & H₄ receptors
• Melatonin MT₁, MT₂, & MT₃ receptors
• Hydroxycarboxylic acid receptors: HCA1, HCA2, & HCA3
• Opioid δ, κ, μ, & nociceptin receptors
• Prostaglandin EP₁, EP₃, FP, & TP receptors
• Short chain fatty acid receptors: FFAR2 & FFAR3
• Somatostatin sst1, sst2, sst3, sst4 & sst5 receptors
• Trace amine-associated receptor 8

See also

• Second messenger system
• G protein-coupled receptor
• Heterotrimeric G protein
• Adenylyl cyclase
• Protein kinase A
• Gs alpha subunit
• Gq alpha subunit
• G12/G13 alpha subunits
• Retina
• Taste

References

1. Gilman AG (1987). "G proteins: transducers of receptor-generated signals". Annual Review of Biochemistry. 56: 615–49. doi:10.1146/annurev.bi.56.070187.003151. PMID 3113327.
2. Rodbell M (June 1995). "Nobel Lecture. Signal transduction: evolution of an idea". Bioscience Reports. 15 (3): 117–33. doi:10.1007/bf01207453. PMC 1519115. PMID 7579038. S2CID 11025853.
3. Kano H, Toyama Y, Imai S, Iwahashi Y, Mase Y, Yokogawa M, et al. (May 2019). "Structural mechanism underlying G protein family-specific regulation of G protein-gated inwardly rectifying potassium channel". Nature Communications. 10 (1): 2008. Bibcode:2019NatCo..10.2008K. doi:10.1038/s41467-019-10038-x. PMC 6494913. PMID 31043612.
4. Pfeuffer T, Helmreich EJ (1988). "Structural and functional relationships of guanosine triphosphate binding proteins". Current Topics in Cellular Regulation. 29: 129–216. doi:10.1016/B978-0-12-152829-4.50006-9. ISBN 9780121528294. PMID 3135154.
5. Ho MK, Wong YH (March 2001). "G(z) signaling: emerging divergence from G(i) signaling". Oncogene. 20 (13): 1615–25. doi:10.1038/sj.onc.1204190. PMID 11313909.

External links

• Gi+alpha+Subunit at the U.S. National Library of Medicine Medical Subject Headings (MeSH)