The inward rectifier K(+) channels function in the regulation of myocardial rhythmicity, vascular tones, epithelial transport, and neuronal excitability. Most of these channels are gated by pH. It is now known that the gating process involves a large number of protein domains and amino acid residues in both N- and C-termini of the channel protein. Experimental evidence suggests that at acidic pH, a few titratable residues are protonated in the C-terminus, leading to its interaction with the N-terminus. The N-C-terminal interaction appears to produce vast conformational changes in the channel protein, especially the M2 and M1 sequences, and closes the channels. Thus, gating of these channels requires the N-C-terminal interaction with protons as mediators.