Two Fundamental Regulatory Factors of the Na+/H+ Exchangers

The Proton and CHP
  • Shigeo Wakabayashi
  • Tianxiang Pang
  • Takashi Hisamitsu
  • Munekazu Shigekawa


The Na+/H+ exchangers (NHEs) are plasma membrane transporters that regulate pH homeostasis, cell volume, and transepithelial Na+ absorption (1, 2, 3, 4). At present, the NHE family includes eight isoforms (NHE1-NHE8) that differ in their tissue and subcellular localizations. An intriguing feature of exchangers is that their activities are controlled by various extrinsic factors, including hormones, growth factors, pharmacological agents, and mechanical stimuli (1, 2, 3, 4). The regulatory mechanisms of NHE 1 and NHE3 isoforms have been studied extensively. For example, NHE1 has been reported to occur via the involvement of a variety of signaling molecules, i.e., calcinuerin B-homologous protein (CHP) (5,6), Ca2+/calmodulin (7,8), 14–3–3 protein (9), Nck-interacting kinase (NIK) (10), and phosphatidylinositol 4,5-bisphosphate (11). Although the interrelationships among these molecules are not known, several transmit signals to the more general NHE1 regulator, the intracellular proton, because many extracellular stimuli control NHE1 activity by changing the apparent affinity for intracellular H+, probably at the level of the allosteric “H+-modifier site” (12, and see references 1–4 for review). Therefore, the cytosolic proton is itself an important regulatory factor. Furthermore, we recently have found that CHP is an essential cofactor for supporting the physiological activity of plasma membrane exchangers (6). In this chapter, we focus on two important cytosolic factors, the proton and CHP.


Cytoplasmic Domain Modifier Site Transport Site Intracellular Proton Renal Brush Border Membrane Vesicle 
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Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Shigeo Wakabayashi
    • 1
  • Tianxiang Pang
    • 1
  • Takashi Hisamitsu
    • 1
  • Munekazu Shigekawa
    • 1
  1. 1.Department of Molecular PhysiologyNational Cardiovascular Research InstituteOsakaJapan

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