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Endocrinology, Vol 133, 713-719, Copyright © 1993 by Endocrine Society


ARTICLES

Structure-function requirements of parathyroid hormone for stimulation of 1,25-dihydroxyvitamin D3 production by rat renal proximal tubules

M Janulis, MS Wong and MJ Favus
Section of Endocrinology, University of Chicago Pritzker School of Medicine, Illinois 60637.

PTH stimulates synthesis and secretion of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] in renal proximal tubule cells through activation of the protein kinase-A (PKA) or the protein kinase-C (PKC) signaling pathway. The relative contribution of the two transducing systems was explored using PTH fragments with selective activation of either PKA or PKC. Rat renal proximal tubules were isolated by Percoll centrifugation, and PKA and PKC activities were measured after treatment with synthetic fragments and analogs of PTH. Rat PTH-(1-34), [Nle8,Nle15,Tyr34]bovine PTH-(3-34), and human PTH-(13-34) increased PKC activity in a dose- dependent manner. All fragments tested stimulated PKC at physiological concentrations (10(-11)-10(-10) M). Rat PTH-(1-34) (10(-7) M) increased PKA activity 4.5-fold, but other fragments failed to stimulate PKA between 10(-12)-10(-6) M. Human PTH-(28-34) stimulation of PKC was variable from experiment to experiment. All four PTH fragments tested increased 1,25-(OH)2D3 secretion by perifused renal proximal tubules at the lowest concentrations that stimulated PKC activity. The adenylate cyclase inhibitor 2',5'-dideoxyadenosine (10(-4) M) reduced PTH-(1-34)- stimulated PKA activity by 60%, but failed to block the rise in 1,25- (OH)2D3 secretion. The results of these studies demonstrate that PTH fragments that contain the PKC translocating domain stimulate 1,25- (OH)2D3 secretion, whereas elimination of the PKA activation domain does not alter the potency of the analogs' 1,25-(OH)2D3-stimulating activity. These results support the concept that PKC translocation may be required for PTH stimulation of 1,25-(OH)2D3 secretion.


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T. M. Murray, L. G. Rao, P. Divieti, and F. R. Bringhurst
Parathyroid Hormone Secretion and Action: Evidence for Discrete Receptors for the Carboxyl-Terminal Region and Related Biological Actions of Carboxyl- Terminal Ligands
Endocr. Rev., February 1, 2005; 26(1): 78 - 113.
[Abstract] [Full Text] [PDF]




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