G protein-gated ion channel
[2] A class known as metabotropic glutamate receptors play a large role in indirect ion channel activation by G proteins.
[3] G protein-gated ion channels are primarily found in CNS neurons and atrial myocytes, and affect the flow of potassium (K+), calcium (Ca2+), sodium (Na+), and chloride (Cl−) across the plasma membrane.
[7] These domains on the N-and C-terminal ends which interact with the G proteins contain certain residues which are critical for the proper activation of the GIRK channel.
[10] Activation of the IKACh channels begins with release of acetylcholine (ACh) from the vagus nerve[9] onto pacemaker cells in the heart.
[10] ACh binds to the M2 muscarinic acetylcholine receptors, which interact with G proteins and promote the dissociation of the Gα subunit and Gβγ-complex.
[14] The G protein inward rectifying K+ channel found in the CNS is a heterotetramer composed of GIRK1 and GIRK2 subunits[4] and is responsible for maintaining the resting membrane potential and excitability of the neuron.
The G proteins couple the inward rectifying K+ channels to the GABAB receptors, mediating a significant part of the GABA postsynaptic inhibition.
[4] Furthermore, GIRKs have been found to play a role in a group of serotonergic neurons in the dorsal raphe nucleus, specifically those associated with the neuropeptide hormone orexin.
The subsequent activation of the GIRK channel mediates hyperpolarization of orexin neurons, which regulate the release of many other neurotransmitters including noradrenaline and acetylcholine.
This short circuit is membrane-delimiting, allowing direct gating of calcium channels by G proteins to produce effects more quickly than the cAMP cascade could.
[13] The activation of α-subunits of G proteins has been shown to cause rapid closing of voltage-dependent Ca2+ channels, which causes difficulties in the firing of action potentials.
[1] This inhibition of voltage-gated Calcium channels by G protein-coupled receptors has been demonstrated in the dorsal root ganglion of a chick among other cell lines.
[20] Patch clamp measurements suggest a direct role for Gα in the inhibition of fast Na+ current within cardiac cells.
[10] Other studies, in CHO cells, have demonstrated a large conductance Cl− channel to be activated differentially by CTX- and PTX-sensitive G proteins.
[4] Epilepsy, chronic pain, and addictive drugs such as cocaine, opioids, cannabinoids, and ethanol all affect neuronal excitability and heart rate.
GIRK channels have been shown to be involved in seizure susceptibility, cocaine addiction, and increased tolerance for pain by opioids, cannabinoids, and ethanol.
Agents that can act as agonists to this binding site can be potentially useful in the creation of drugs for the treatment of neurological disorders such as epilepsy in which neuronal firing exceeds normal levels.
Studies have found that recombinant mice overexpressing GIRK2 subunits show altered responses to drugs that activate G protein-gated K+ channels.
Atrial fibrillation (abnormal heart rhythm) is associated with shorter action potential duration and believed to be affected by the G protein-gated K+ channel, IK,ACh.
It has been shown that in chronic atrial fibrillation there an increase in this inwardly rectifying current because of constantly activated IK,ACh channels.
[30] These specific channels have been the target of recent studies dealing with genetic variance and sensitivity to opioid analgesics due to their role in opioid-induced analgesia.
[31] Furthermore, studies have shown that G proteins, specifically the Gi alpha subunit, directly activate GIRKs which were found to participate in propagation of morphine-induced analgesia in inflamed spines of mice.
