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Endocrinology Vol. 140, No. 1 301-309
Copyright © 1999 by The Endocrine Society

ARTICLES

Cell-Specific Signaling and Structure-Activity Relations of Parathyroid Hormone Analogs in Mouse Kidney Cells1

Peter A. Friedman, Frank A. Gesek, Paul Morley, James F. Whitfield and Gordon E. Willick

Departments of Pharmacology and of Medicine, University of Pittsburgh School of Medicine (P.A.F.), Pittsburgh, Pennsylvania 15261; the Department of Pharmacology and Toxicology, Dartmouth Medical School (F.A.G.), Hanover, New Hampshire 03755; and the Institute for Biological Sciences, National Research Council of Canada (P.M., J.F.W., G.E.W.), Ottawa, Ontario, Canada K1A OR6

Address all correspondence and requests for reprints to: Peter A. Friedman, Ph.D., Department of Pharmacology, University of Pittsburgh School of Medicine, E-1347 Biomedical Science Tower, Pittsburgh, Pennsylvania 15261. E-mail: PAF10{at}pitt.edu

PTH is an 84-amino acid protein. Occupancy of its cognate receptor generally results in activation of adenylyl cyclase and/or phosphoinositide-specific phospholipase Cß (PLCß). In the kidney, PTH receptors are present on proximal and distal tubule cells. In proximal tubules, PTH induces calcium signaling, typified by a transient rise in intracellular calcium ([Ca2+]i) and inositol trisphosphate formation, but does not affect calcium absorption. By contrast, in distal tubules, PTH increases calcium absorption that is associated with a slow and sustained rise in [Ca2+]i, but does not stimulate phospholipase C (PLC) or cause inositol trisphosphate accumulation. Nonetheless, stimulation of distal calcium transport requires activation of protein kinase C (PKC) and protein kinase A. We now characterize the origin of the differential effects of ligand occupancy by using synthetic human PTH analogs that preferentially activate adenylyl cyclase and/or PLCß. We further tested the hypothesis that phospholipase D is responsible for PKC activation in distal tubule cells. PTH-(1–31) increased [Ca2+]i in distal tubule but not in proximal tubule cells, whereas PTH-(3–34) caused a partial increase in [Ca2+]i in proximal cells, but had no effect in distal cells. PTH-(7–34) blocked increases in [Ca2+]i in distal tubule cells stimulated by PTH-(1–34) and PTH-(1–31). The PLC inhibitor U73122 abolished the PTH-induced rise in [Ca2+]i and inositol trisphosphate formation by proximal tubule cells, but had no effect on PTH-stimulated Ca2+ uptake by distal tubule cells. These results support the view that activation of PKC by PTH in distal tubule cells does not involve PLCß. PTH did, however, activate phospholipase D with attendant formation of diacylglycerol in distal cells. As activation of PKC is required for induction of calcium transport by PTH, we conclude that PTH receptors are capable of activating multiple phospholipases and that the structural requirements for such activation differ in proximal and distal tubule cells.




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