Na+/H+ exchanger: proton modifier site regulation of activity

The Na+/H+ exchangers (NHE1-6) are integral plasma membrane proteins that c atalyze the exchange of extracellular Na+ for intracellular H+. In addition to Na+ and H+ transport sites, NHE has an intracellular allosteric H+ modi fier site that increases exchange activity when occupied by H+. NHE activit y is also subject to control by a variety of extrinsic factors including ho rmones, growth factors, cytokines, and pharmacological agents. Many of thes e factors, working through second messenger pathways acting directly or ind irectly on NHE, regulate NHE activity by shifting the apparent affinity of the H+ modifier site to more alkaline or more acid pH. The underlying molec ular mechanisms involved in the activation of NHE by the H+ modifier site a re poorly understood at this time, but likely involve slow protein conforma tional changes within a NHE oligomer. In this paper, we present initial exp eriments measuring intracellular pH-dependent transition rates between acti ve and inactive oligomeric conformations and describe how these transition rates may be important for overall regulation of NHE activity.