The plasmamembrane calmodulin-dependent calcium pump: a major regulator ofnitric oxide synthase I

Citation
K. Schuh et al., The plasmamembrane calmodulin-dependent calcium pump: a major regulator ofnitric oxide synthase I, J CELL BIOL, 155(2), 2001, pp. 201-205
Citations number
30
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cell & Developmental Biology
Journal title
JOURNAL OF CELL BIOLOGY
ISSN journal
0021-9525 → ACNP
Volume
155
Issue
2
Year of publication
2001
Pages
201 - 205
Database
ISI
SICI code
0021-9525(20011015)155:2<201:TPCCPA>2.0.ZU;2-R
Abstract
The plasma membrane calcium/calmodulin-dependent calcium ATPase (PMCA) (Shu ll, G.E., and J. Greeb. 1988. J. Biol. Chem. 263:8646-8657; Verma, A.K., A. G. Filoteo, D.R. Stanford, E.D. Wieben, J.T. Penniston, E.E. Strehler, R. F ischer, R. Heim, G. Vogel, S. Mathews, et al. 1988. J. Biol. Chem. 263:1415 2-14159; Carafoli, E. 1997. Basic Res. Cardiol. 92:59-61) has been proposed to be a regulator of calcium homeostasis and signal transduction networks of the cell. However, little is known about its precise mechanisms of actio n. Knock-out of (mainly neuronal) isoform 2 of the enzyme resulted in heari ng loss and balance deficits due to severe inner ear defects, affecting for mation and maintenance of otoconia (Kozel, P.J., R.A. Friedman, L.C. Erway, E.N. Yamoah, L.H. Liu, T. Riddle, J.J. Duffy, T. Doetschman, M.L. Miller, E.L. Cardell, and G.E. Shull. 1998. J. Biol. Chem. 273:18693-18696). Here w e demonstrate that PMCA 4b is a negative regulator of nitric oxide synthase 1 (NOS-1, nNOS) in HEK293 embryonic kidney and neuro-2a neuroblastoma cell models. Binding of PMCA 4b to NOS-1 was mediated by interaction of the COO H-terminal amino acids of PMCA 4b and the PDZ domain of NOS-1 (PDZ: PSD 95/ Dlg/ZO-1 protein domain). Increasing expression of wild-type PMCA 4b (but n ot PMCA mutants unable to bind PDZ domains or devoid of Ca2+-transporting a ctivity) dramatically downregulated NO synthesis from wild-type NOS-1. A NO S-1 mutant lacking the PDZ domain was not regulated by PMCA, demonstrating the specific nature of the PMCA-NOS-1 interaction. Elucidation of PMCA as a n interaction partner and major regulator of NOS-1 provides evidence for a new dimension of integration between calcium and NO signaling pathways.