Gi alpha subunit

Function

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. 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. When not stimulated by a receptor, Gα is bound to GDP and to Gβγ to form the inactive G protein trimer. 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. 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). 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.

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.

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