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Molecular Endocrinology, doi:10.1210/me.2003-0043
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Molecular Endocrinology 17 (11): 2355-2364
Copyright © 2003 by The Endocrine Society

Na+/H+ Exchanger-Regulatory Factor 1 Mediates Inhibition of Phosphate Transport by Parathyroid Hormone and Second Messengers by Acting at Multiple Sites in Opossum Kidney Cells

Matthew J. Mahon, Judith A. Cole, Eleanor D. Lederer and Gino V. Segre

Endocrine Unit (M.J.M., G.V.S.), Massachusetts General Hospital, Boston, Massachusetts 02114; Department of Pharmacology (J.A.C.), University of Missouri School of Medicine, Columbia, Missouri 65212; Kidney Disease Program (E.D.L.), University of Louisville, Louisville, Kentucky 40202

Address all correspondence and requests for reprints to: Gino V. Segre, M.D., Endocrine Unit, Wellman 501, Massachusetts General Hospital, 50 Blossom Street, Boston, Massachusetts 02114. E-mail: segre{at}helix.mgh.harvard.edu.

The opossum kidney (OK) line displays PTH-mediated activation of adenylyl cyclase and phospholipase C and inhibition of phosphate (Pi) uptake via regulation of the type IIa sodium-phosphate cotransporter, consistent with effects in vivo. OKH cells, a subclone of the OK cell line, robustly activates PTH-mediated activation of adenylyl cyclase, but is defective in PTH-mediated inhibition of sodium-phosphate cotransport and signaling via phospholipase C. Compared with wild-type OK cells, OKH cells express low levels of the Na+/H+ exchanger regulatory factor 1 (NHERF-1). Stable expression of NHERF-1 in OKH cells (OKH-N1) rescues the PTH-mediated inhibition of sodium-phosphate cotransport. NHERF-1 also restores the capacity of 8-bromo-cAMP and forskolin to inhibit Pi uptake, but the PTH dose-response for cAMP accumulation and inhibition of Pi uptake differ by 2 orders of magnitude. NHERF-1, in addition, modestly restores phorbol ester-mediated inhibition of Pi uptake, which is much weaker than that elicited by PTH. A poor correlation exists between the inhibition of Pi uptake mediated by PTH (~60%) and the inhibition mediated by phorbol 12-myristate 13-acetate (~30%) and the ability of these molecules to activate the protein kinase C-responsive reporter gene. Furthermore, we show that NHERF-1 directly interacts with type IIa cotransporter in OK cells. Although, PTH-mediated inhibition of Pi uptake in OK cells is largely NHERF-1 dependent, the signaling pathway(s) by which this occurs is still unclear. These pathways may involve cooperativity between cAMP- and protein kinase C-dependent pathways or activation/inhibition of an unrecognized NHERF-1-dependent pathway(s).




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