Gating of inward-rectifier K+ channels by intracellular pH

Inward rectifier K+ channels of the K(ir)1.1 (ROMK) and K(ir)4.1 subtype ar e predominantly expressed in epithelial cells where they are responsible fo r K+ transport across the plasma membrane. Uniquely among the members of th e K-ir family, these channels are gated by intracellular pH in the physiolo gical range. pH-gating involves structural rearrangements in cytoplasmic do mains and the P-loop of the K-ir protein. The energy for the gating transit ion is delivered by protonation of a lysine residue that is located prior t o the first transmembrane segment and serves as a 'pH sensor'. The anomalou s titration required for lysine operating in the neutral pH range results f rom its close interaction with two positively charged arginines from the di stant N- and C-termini termed the R/K/R triad. Disturbance of this triad as results from a number of point mutations found in patients with hyperprost aglandin E syndrome (HPS) increases the pK(a) of the pH sensor and results in channels being permanently inactivated under physiological conditions. This article will focus on the mechanism of pH-gating, its implications for the tertiary structure of Ki, proteins and on its significance for the pat hogenesis of HPS.