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© The Rockefeller University Press, 0021-9525/2001/10/201 $5.00
The Journal of Cell Biology, Volume 155, Number 2, October 15, 2001 201-206

The plasmamembrane calmodulin–dependent calcium pump

Kai Schuh¹, Stjepan Uldrijan², Myriam Telkamp¹, Nicola Röthlein¹ and Ludwig Neyses³

¹ Department of Medicine, University of Wuerzburg, D-97080 Wuerzburg, Germany
² Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
³ Department of Medicine, University of Manchester, M13 9WL Manchester, United Kingdom

Address correspondence to Ludwig Neyses, University Department of Medicine, Manchester Royal Infirmary, Oxford Road, M13 9WL Manchester, UK. Tel.: (44) 161-276-6631. Fax: (44) 161-276-5152. E-mail: ludwig.neyses{at}mhc.cmht.nwest.nhs.uk

The plasma membrane calcium/calmodulin-dependent calcium ATPase (PMCA) (Shull, 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. Fischer, R. Heim, G. Vogel, S. Mathews, et al. 1988. J. Biol. Chem. 263:14152–14159; 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 action. Knock-out of (mainly neuronal) isoform 2 of the enzyme resulted in hearing loss and balance deficits due to severe inner ear defects, affecting formation 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 we demonstrate that PMCA 4b is a negative regulator of nitric oxide synthase I (NOS-I, nNOS) in HEK293 embryonic kidney and neuro-2a neuroblastoma cell models. Binding of PMCA 4b to NOS-I was mediated by interaction of the COOH-terminal amino acids of PMCA 4b and the PDZ domain of NOS-I (PDZ: PSD 95/Dlg/ZO-1 protein domain). Increasing expression of wild-type PMCA 4b (but not PMCA mutants unable to bind PDZ domains or devoid of Ca²⁺-transporting activity) dramatically downregulated NO synthesis from wild-type NOS-I. A NOS-I mutant lacking the PDZ domain was not regulated by PMCA, demonstrating the specific nature of the PMCA–NOS-I interaction. Elucidation of PMCA as an interaction partner and major regulator of NOS-I provides evidence for a new dimension of integration between calcium and NO signaling pathways.

Key Words: PMCA; NOS; calcium; nitric oxide; PDZ domain

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