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.

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

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.

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

• 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^[6])
• Chemokine CXCR4 receptor
• Dopamine D₂, D₃, D₄
• GABA_B receptor
• Glutamate mGlu₂, mGlu₃, mGlu₄, mGlu₆, mGlu₇, & mGlu₈ 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
• Serotonin 5-HT₁ & 5-HT₅ receptors
• Short chain fatty acid receptors: FFAR2 & FFAR3
• Somatostatin sst1, sst2, sst3, sst4 & sst5 receptors
• Trace amine-associated receptor 8

• 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