Answer: Gi proteins can decrease cellular excitability by decreasing cyclic AMP, leading to a decrease in opening of cyclic nucleotide gated ion channels or AMPA type glutamate receptor phosphorylation.
G-protein coupled receptors, also called GPCRs, are proteins that are embedded in the cell membrane. They are important for cellular transduction, the process by which a signal from the extracellular space is conveyed to the cell through activation of some molecular signaling cascade. For example, neurotransmission can occur by activation of GPCRs; this type of receptor is called a metabotropic receptor.
G-proteins themselves are a complex of three proteins that utilize GTP as part of the signaling pathway. G-proteins trigger a downstream chain reaction of other proteins, one of them being the alpha subunit. When GTP binds to the alpha subunit, it becomes active and dissociates from the beta/gamma subunit.
G alpha subunits are generally named after their function. In a Galpha i subunit, activation can inhibit the activity of the enzyme adenylyl cyclase (sometimes called adenylate cyclase), which decreases the production of cyclic AMP from ATP. Because cyclic AMP (cAMP) increases excitability, activation of Galpha i will decrease cell excitation.
CAMP itself is a second messenger molecule. It can lead to an opening of cyclic nucleotide gated channels, which are commonly nonselective ion channels. Opening these channels leads to an excitatory inward current as sodium enters the cell. Therefore, when the the Gi protein decreases adenylyl cyclase activity which decreases the concentration of cAMP, there is less activation of the the cyclic nucleotide gated channels.
Gi proteins generally work opposite of Gs proteins. The “i” stands for inhibitory, while the “s” stands for stimulatory. They both act at the adenylyl cyclase enzymes.
Many neurotransmitters systems are coupled with Gi proteins, for example:
Glutamate receptors: mGluR2 and mGluR3
Acetylcholine receptors: M2 and M4
Cannabinoid receptors: CB1 and CB2
Dopamine receptors: D2, D3, and D4
Opioid receptors: delta opioid receptors (DOR), mu opioid receptors (MOR), kappa opioid receptors (KOR)
Serotonin receptors: 5-HT1 and 5-HT5