Two Fundamental Regulatory Factors of the Na+/H+ Exchangers
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.
KeywordsCytoplasmic Domain Modifier Site Transport Site Intracellular Proton Renal Brush Border Membrane Vesicle
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- 13.Pang, T, Wakabayashi, S, Shigekawa, M. Expression of calcineurin B homologous protein 2 protects serum deprivation-induced cell death by serum-independent activation of Na+/H+ exchanger J Biol Chem 2002 (in press)Google Scholar
- 17.Out, K, Kinsella, JL, Heller, P, Froehlich, J. Sodium dependence of the Na+-H+ exchanger in the pre-steady state. Implications for the exchange mechanism. J Biol Chem 268:3184–3193,1993Google Scholar
- 28.Matsumoto, M, Miyake, Y, Nagita, M, Inoue, H, Shitakubo, D, Takemoto, K, Ohtsuka, C, Murakami, H, Nakamura, N, Kanazawa, H. A serine/threonine kinase which causes apoptosis-Like cell death Interacts with a calcineurin B-Like protein capable of binding Na+/H+ Exchanger J BioChem (Tokyo) 130:217–225, 2001PubMedCrossRefGoogle Scholar
- 30.Kissinger, CR, Parge, HE, Knighton, DR, Lewis, CT, Pelletier, LA, Tempczyk, A, Kalish, VJ, Tucker, KD, Showalter, RE, Moomaw, EW, Gastinel, LN, Habuka, N, Chen, X, Maldonado, F, Barker, JE, Bacquet, R, Villafranca, JE. Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex. Nature 378: 641–644, 1995PubMedCrossRefGoogle Scholar
- 32.Inoue, H, Nakamura, Y, Nakita, M, Takai, T, Masuda, M, Nakamura, N, Kanazawa, H. J Biochem (Tokyo) in press, 2002Google Scholar
- 36.Reshkin, SJ, Bellizzi, A, Caldeira, S, Albarani, V, Malanchi, I, Poignee, M, Alunni-Fabbroni, M, Casavola, V, Tommasino, M. Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEB J 14: 2185–2197,2000PubMedCrossRefGoogle Scholar
- 38.McLean, LA, Roscoe, J, Jorgensen, NK, Gorin, FA, Cala, PM. Malignant gliomas display altered pH regulation by NHE1 compared with nontransformed astrocytes. Am J Physiol 278: C676–C688, 2000Google Scholar
- 39.Reshkin, SJ, Bellizzi, A, Albarani, V, Guerra, L, Tommasino, M, Paradiso, A, Casavola, V. Phosphoinositide 3-kinase Is involved in the tumor-specific activation of human breast cancer cell Na+/H+ exchange, motility, and invasion induced by serum deprivation. J Biol Chem 275:5361–5369, 2000PubMedCrossRefGoogle Scholar