Inwardrectifier

Inward rectifiers, or inward rectifier potassium channels (Kir), are a family of potassium-selective ion channels that preferentially pass current into the cell rather than out of it at potentials near the resting membrane potential. This inward preference arises because outward current is strongly attenuated at positive potentials.

Mechanism: Rectification is mainly due to voltage-dependent block of the channel pore by intracellular polyamines and magnesium ions when the membrane is depolarized. These blockers occlude outward K+ flux, while inward current at hyperpolarized potentials remains relatively preserved. Some Kir channels are also regulated by phosphatidylinositol 4,5-bisphosphate (PIP2) and, in the case of G protein–gated channels, by G-protein signaling.

Structure and diversity: Kir channels form tetramers and are encoded by the KCNJ gene family. Major subfamilies include Kir2.x (inwardly rectifying channels in heart and muscle), Kir3.x (GIRK channels activated by G protein–coupled receptors), Kir4.x and Kir5.x (found in glia and epithelia), and Kir6.x (part of ATP-sensitive K+ channels that partner with SUR subunits). The different subtypes tailor inward rectification to specific tissues and physiological roles.

Physiological roles: Kir channels help set and stabilize the resting membrane potential, influence repolarization and excitability, and contribute to signaling pathways in various cells. GIRK channels mediate autonomic regulation of heart rate and neuronal inhibition, while KATP channels couple cellular metabolism to electrical activity in pancreatic beta cells and cardiac tissue.

Pharmacology and regulation: Many Kir channels are blocked by intracellular polyamines and Mg2+, and externally by cesium or barium. Channel activity can be modulated by ligands, lipid interactions (notably PIP2), and, for GIRK channels, G-protein signaling.

Clinical relevance: Dysfunction or mutations in Kir channels are associated with a range of cardiac and neurological disorders, reflecting their essential role in excitable tissues.