Regulation of ion transport from within ion transit pathways.

All cells must control the activities of their ion channels and transporters to maintain physiologically appropriate gradients of solutes and ions. The complexity of underlying regulatory mechanisms is staggering, as exemplified by insulin regulation of transporter trafficking. Simpler strategies occur in single-cell organisms, where subsets of transporters act as solute sensors to regulate expression of their active homologues. This Viewpoint highlights still simpler mechanisms by which Na transporters use their own transport sites as sensors for regulation. The underlying principle is inherent to Na/K pumps in which aspartate phosphorylation and dephosphorylation are controlled by occupation of transport sites for Na and K, respectively. By this same principle, Na binding to transport sites can control intrinsic inactivation reactions that are in turn modified by extrinsic signaling factors. Cardiac Na/Ca exchangers (NCX1s) and Na/K pumps are the best examples. Inactivation of NCX1 occurs when cytoplasmic Na sites are fully occupied and is regulated by lipid signaling. Inactivation of cardiac Na/K pumps occurs when cytoplasmic Na-binding sites are not fully occupied, and inactivation is in turn regulated by Ca signaling. Potentially, Na/H exchangers (NHEs) and epithelial Na channels (ENaCs) are regulated similarly. Extracellular protons and cytoplasmic Na ions oppose secondary activation of NHEs by cytoplasmic protons. ENaCs undergo inactivation as cytoplasmic Na rises, and small diffusible molecules of an unidentified nature are likely involved. Multiple other ion channels have recently been shown to be regulated by transiting ions, thereby underscoring that ion permeation and channel gating need not be independent processes.