NHE3 regulatory complexes

Abstract

SummaryThe epithelial brush border Na/H exchanger NHE3 is active under basal conditions and functions as part of neutral NaCl absorption in the intestine and renal proximal tubule, where it accounts for the majority of total Na absorbed. NHE3 is highly regulated. Both stimulation and inhibition occur post-prandially. This digestion related regulation of NHE3 is mimicked by multiple extracellular agonists and intracellular second messengers. The regulation of NHE3 depends on its C-terminal cytoplasmic domain, which acts as a scaffold to bind multiple regulatory proteins and links NHE3 to the cytoskeleton. The cytoskeletal association occurs by both direct binding to ezrin and by indirect binding via ezrin binding to the C-terminus of the multi-PDZ domain containing proteins NHERF1 and NHERF2. This is a review of the domain structure of NHE3 and of the scaffolding function and role in the regulation of NHE3 of the NHE3 C-terminal domain.

Dynamic Na+-H+ Exchanger Regulatory Factor-1 Association and Dissociation Regulate Parathyroid Hormone Receptor Trafficking at Membrane Microdomains

“…The sodium-hydrogen exchanger-3 (NHE-3), which like the PTHR possesses an atypical PDZ recognition motif, STHM, also binds directly to ezrin (50). Furthermore, NHE-3 binds both to NHERF1 and ezrin to form a ternary complex (51). The presence of these low affinity, atypical motifs in the PTHR and NHE-3 in conjunction with their ability to form ternary complexes raises the possibility that NHERF1 facilitates receptor/transporter and ezrin-actin cytoskeleton interactions rather than forming a stable component of the complex.…”

NHE3 Activity Is Dependent on Direct Phosphoinositide Binding at the N Terminus of Its Intracellular Cytosolic Region

“…As shown in Fig. 1A, these clusters were located C-terminal to the putative calcineurin homologous protein binding area of NHE3, which we predicted by homology to the NHE1 calcineurin homologous protein-binding site, the structure of which had been solved (24,25 , which had been shown by mutagenesis to be part of the NHE3 intracellular pH sensor (26).…”

Calmodulin Kinase II Constitutively Binds, Phosphorylates, and Inhibits Brush Border Na+/H+ Exchanger 3 (NHE3) by a NHERF2 Protein-dependent Process

“…We have estimated that at any time up to 20 proteins of an average size of 50 kDa associate with NHE3, only some of which have been identified (14). The NHE3 C-terminal domain, which is necessary for CaMKII binding is aa 586 -605, which is predicted by multiple modeling programs to be ␣-helical.…”

“…NHE3 is acutely regulated predominantly by changes in its V max by processes that involve changes in its continual trafficking to/from the plasma membrane by endocytosis and exocytosis; however, some of its regulation predominantly involves changes in the NHE3 turnover number (7). Regulation of Na ϩ /H ϩ exchange activity involves several distinct domains in the NHE3 C terminus (7)(8)(9)(10)(11)(12)(13)(14). NHE3 exists as a member of large multiprotein complexes with sizes of up to 1-2 MDa rather than its predicted size of 87 kDa.…”

“…Its C-terminal binding partners include the multi-PDZ domain containing Na ϩ /H ϩ exchanger regulatory factor gene family members (NHERF1-4), CK2, phospholipase C␥, calmodulin, megalin, dipeptidyl peptidase IV, calcineurin homologous protein, and ezrin (7)(8)(9)(10)(11)(12)(13)(14). At least six of these regulatory proteins (NHERF1-4, CK2, and phospholipase C␥) directly associate with NHE3 via a small, putative ␣-helical domain of NHE3, between amino acids 586 and 605 (14). These interactions modulate acute stimulation and inhibition of NHE3 activity, which mimic changes that occur in digestive physiology.…”