G protein-gated ion channel
G protein-gated ion channels are a family of transmembrane
Overview of mechanisms and function
Generally, G protein-gated ion channels are specific
G protein-gated ion channels are associated with a specific type of G protein-coupled receptor. These ion channels are transmembrane ion channels with selectivity filters and a G protein binding site. The GPCRs associated with G protein-gated ion channels are not involved in signal transduction pathways. They only directly activate these ion channels using effector proteins or the G protein subunits themselves (see picture). Unlike most effectors, not all G protein-gated ion channels have their activity mediated by Gα of their corresponding G proteins. For instance, the opening of inwardly rectifying K+ (GIRK) channels is mediated by the binding of Gβγ.[3]
G protein-gated ion channels are primarily found in
Types of G Protein-gated ion channels
Potassium channels
Structure
Four G protein gated
The four GIRK subunits are 80-90% similar in their pore-forming and transmembrane domains, a feature accountable by the similarities in their structures and sequences. GIRK2, GIRK3, and GIRK4 share an overall identity of 62% with each other, while GIRK1 only shares 44% identity with the others.
Subtypes and respective functions
- GIRKs found in the heart
One G protein-gated potassium channel is the inward-rectifing potassium channel (IKACh) found in cardiac muscle (specifically, the sinoatrial node and atria),[8] which contributes to the regulation of heart rate.[9] These channels are almost entirely dependent on G protein activation, making them unique when compared to other G protein-gated channels.[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.[11] IKACh is composed of two homologous GIRK channel subunits: GIRK1 and GIRK4. The Gβγ-complex binds directly and specifically to the IKACh channel through interactions with both the GIRK1 and GIRK4 subunits.[12] Once the ion channel is activated, K+ ions flow out of the cell and cause it to hyperpolarize.[13] In its hyperpolarized state, the neuron cannot fire action potentials as quickly, which slows the heartbeat.[14]
- GIRKs found in the brain
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.[9] Studies have shown the largest concentrations of the GIRK1 and GIRK2 subunits to be in the dendritic areas of neurons in the CNS.[4] These areas, which are both extrasynaptic (exterior to a synapse) and perisynaptic (near a synapse), correlate with the large concentration of GABAB receptors in the same areas. Once the GABAB receptors are activated by their ligands, they allow for the dissociation of the G protein into its individual α-subunit and βγ-complex so it can in turn activate the K+ channels. 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
Calcium channels
Structure
In addition to the subset of potassium channels that are directly gated by G proteins, G proteins can also directly gate certain calcium ion channels in neuronal cell membranes. Although membrane ion channels and protein
Function
Several high-threshold, slowly inactivating calcium channels in neurons are regulated by G proteins.[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.[13] Further studies have indicated roles for both Gα and Gβγ subunits in the inhibition of Ca2+ channels. The research geared to defining the involvement of each subunit, however, has not uncovered the specificity or mechanisms by which Ca2+ channels are regulated.
The
Sodium channels
Patch clamp measurements suggest a direct role for Gα in the inhibition of fast Na+ current within cardiac cells.[21] Other studies have found evidence for a second-messenger pathway which may indirectly control these channels.[22] Whether G proteins indirectly or directly activate Na+ ion channels not been defined with complete certainty.
Chloride channels
Chloride channel activity in epithelial and cardiac cells has been found to be G protein-dependent. However, the cardiac channel that has been shown to be directly gated by the Gα subunit has not yet been identified. As with Na+ channel inhibition, second-messenger pathways cannot be discounted in Cl− channel activation.[23]
Studies done on specific Cl− channels show differing roles of G protein activation. It has been shown that G proteins directly activate one type of Cl− channel in skeletal muscle.[10] Other studies, in CHO cells, have demonstrated a large conductance Cl− channel to be activated differentially by CTX- and PTX-sensitive G proteins.[10] The role of G proteins in the activation of Cl− channels is a complex area of research that is ongoing.
Clinical significance and ongoing research
Mutations in G proteins associated with G protein-gated ion channels have been shown to be involved in diseases such as epilepsy, muscular diseases, neurological diseases, and chronic pain, among others.[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.[24] This connection suggests that GIRK channel modulators may be useful therapeutic agents in the treatment of these conditions. GIRK channel inhibitors may serve to treat addictions to cocaine, opioids, cannabinoids, and ethanol while GIRK channel activators may serve to treat withdrawal symptoms.[24]
Alcohol intoxication
Breast cancer
Studies have shown that a link exists between channels with GIRK1 subunits and the beta-adrenergic receptor pathway in breast cancer cells responsible for growth regulation of the cells. Approximately 40% of primary human breast cancer tissues have been found to carry the mRNA which codes for GIRK1 subunits.[27] Treatment of breast cancer tissue with alcohol has been shown to trigger increased growth of the cancer cells. The mechanism of this activity is still a subject of research.[27]
Down syndrome
Altered cardiac regulation is common in adults diagnosed with Down syndrome and may be related to G protein-gated ion channels. The KCNJ6 gene is located on chromosome 21 and encodes for the GIRK2 protein subunit of G protein-gated K+ channels.[28] People with Down Syndrome have three copies of chromosome 21, resulting in an overexpression of the GIRK2 subunit. Studies have found that recombinant mice overexpressing GIRK2 subunits show altered responses to drugs that activate G protein-gated K+ channels. These altered responses were limited to the sino-atrial node and atria, both areas which contain many G protein-gated K+ channels.[28] Such findings could potentially lead to the development of drugs that can help regulate the cardiac sympathetic-parasympathetic imbalance in Down Syndrome adults.
Chronic atrial fibrillation
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.[29] The IK,ACh channel, when activated by G proteins, allows for the flow of K+ across the plasma membrane and out of the cell. This current hyperpolarizes the cell, thus terminating the action potential. It has been shown that in chronic atrial fibrillation there an increase in this inwardly rectifying current because of constantly activated IK,ACh channels.[29] Increase in the current results in shorter action potential duration experienced in chronic atrial fibrillation and leads to the subsequent fibrillating of the cardiac muscle. Blocking IK,ACh channel activity could be a therapeutic target in atrial fibrillation and is an area under study.
Pain management
GIRK channels have been demonstrated in vivo to be involved in opioid- and ethanol-induced analgesia.[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. Several studies have shown that when opioids are prescribed to treat chronic pain, GIRK channels are activated by certain GPCRs, namely opioid receptors, which leads to the inhibition of nociceptive transmission, thus functioning in pain relief.[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.[32] Research pertaining to chronic pain management continues to be performed in this field.
See also
References
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