G protein-gated ion channels are a family of transmembrane ion channels in neurons and atrial myocytes that are directly gated by G proteins.
Overview of mechanisms and function Generally, G protein-gated ion channels are specific ion channels located in the plasma membrane of cells that are directly activated by a family of associated proteins. Ion channels allow for the selective movement of certain ions across the plasma membrane in cells. More specifically, in nerve cells, along with ion transporters, they are responsible for maintaining the electrochemical gradient across the cell. G proteins are a family of intracellular proteins capable of mediating signal transduction pathways. Each G protein is a heterotrimer of three subunits: α-, β-, and γ- subunits. The α-subunit (Gα) typically binds the G protein to a transmembrane receptor protein known as a G protein-coupled receptor, or GPCR. This receptor protein has a large, extracellular binding domain which will bind its respective ligands (e.g. neurotransmitters and hormones). Once the ligand is bound to its receptor, a conformational change occurs. This conformational change in the G protein allows Gα to bind GTP. This leads to yet another conformational change in the G protein, resulting in the separation of the βγ-complex (Gβγ) from Gα. At this point, both Gα and Gβγ are active and able to continue the signal transduction pathway. Different classes of G protein-coupled receptors have many known functions including the cAMP and Phosphatidylinositol signal transduction pathways. A class known as metabotropic glutamate receptors play a large role in indirect ion channel activation by G proteins. These pathways are activated by second messengers which initiate signal cascades involving various proteins which are important to the cell's response. 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. 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.
Types of G Protein-gated ion channels
Potassium channels
Structure Four G protein gated inwardly-rectifying potassium (GIRK) channel subunits have been identified in mammals: GIRK1, GIRK2, GIRK3, and GIRK4. The GIRK subunits come together to form GIRK ion channels. These ion channels, once activated, allow for the flow of potassium ions (K+) from the extracellular space surrounding the cell across the plasma membrane and into the cytoplasm. Each channel consists of domains which span the plasma membrane, forming the K+-selective pore region through which the K+ ions will flow. Both the N-and C-terminal ends of the GIRK channels are located within the cytoplasm. These domains interact directly with the βγ-complex of the G protein, leading to activation of the K+ channel. . 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. In GIRK4, the N-terminal residue is His-64 and the C-terminal residue is Leu-268; in GIRK1 they are His-57 and Leu-262, respectively. Mutations in these domains lead to the channel's desensitivity to the βγ-complex and therefore reduce the activation of the GIRK channel. 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. Because of their similarity, the GIRK channel subunits can come together easily to form heteromultimers (a protein with two or more different polypeptide chains). GIRK1, GIRK2, and GIRK3 show abundant and overlapping distribution in the central nervous system (CNS) while GIRK1 and GIRK4 are found primarily in the heart. GIRK1 combines with GIRK2 in the CNS and GIRK4 in the atrium to form heterotetramers; each final heterotetramer contains two GIRK1 subunits and two GIRK2 or GIRK4 subunits. GIRK2 subunits can also form homotetramers in the brain, while GIRK4 subunits can form homotetramers in the heart. GIRK1 subunits have not been shown to be able to form functional homotetramers. Though GIRK3 subunits are found in the CNS, their role in forming functional ion channels is still unknown.
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), which contributes to the regulation of heart rate. These channels are almost entirely dependent on G protein activation, making them unique when compared to other G protein-gated channels. Activation of the IKACh channels begins with release of acetylcholine (ACh) from the vagus nerve onto pacemaker cells in the heart. ACh binds to the M2 muscarinic acetylcholine receptors, which interact with G proteins and promote the dissociation of the Gα subunit and Gβγ-complex. 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. Once the ion channel is activated, K+ ions flow out of the cell and cause it to hyperpolarize. In its hyperpolarized state, the neuron cannot fire action potentials as quickly, which slows the heartbeat.
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