Figure 1.

Putative topologic model of an 815-amino acid Na⁺-H⁺ exchanger isoform-1. Depicted are 12 transmembrane-spanning segments and a 315-amino acid cytoplasmic hydrophilic carboxyl terminus domain (COOH). The transmembrane domain includes the intracellular H⁺-sensor site, the functional ion exchange site, and the site where inhibitors bind. The cytoplasmic domain includes sites for regulation via phosphorylation-dependent (P) and phosphorylation-independent mechanisms. Depicted are CaM-A and CaM-B representing high- and low-affinity binding sites for the Ca²⁺ binding protein calmodulin and CHP, denoting calcineurin homologous protein. Not shown are additional regulatory sites in the cytoplasmic domain for the extracellular signal regulated kinase (ERK1/2), p38 mitogen-activated protein kinase (MAPK), ribosomal S6 kinase (RSK), RhoA kinase, and the tyrosine kinase 2 (Pyk2).