PARATHYROID-HORMONE (PTH) PTH-RELATED PROTEIN (PTHRP) RECEPTOR AND ITS MESSENGER-RIBONUCLEIC-ACID IN RAT AORTIC VASCULAR SMOOTH-MUSCLE CELLS AND UMR OSTEOBLAST-LIKE CELLS - CELL-SPECIFIC REGULATION BY ANGIOTENSIN-II AND PTHRP/

PTH-related protein (PTHrP) is produced in vascular smooth muscle, whe re it is believed to act as a local vasorelaxant by activating either the classical PTH or a unique PTHrP receptor. We used a newly cloned c omplementary DNA encoding the rat PTH/PTHrP receptor to study the expr ession of its messenger RNA (mRNA) in primary aortic vascular smooth m uscle cells (VSMC) and in UMR-106 osteoblast-like cells under basal co nditions and in response to treatment with agonists. Both cell types e xpressed a 2.4-kilobase PTH/PTHrP receptor mRNA transcript and exhibit ed hormone-induced desensitization of PTHrP-(1-34)NH2-stimulated cAMP. In VSMC, angiotensin-II, which induces PTHrP expression, also rapidly (30 min) desensitized the cAMP response and down-regulated (75-90%) r eceptor mRNA within 1 h. Treatment of cells with phorbol 12-myristate 13-acetate (0.1 mu M) mimicked these effects, whereas neither PTHrP-(1 -34)NH2, forskolin, nor (Bu)(2)cAMP altered receptor mRNA expression. By contrast, in UMR-106 cells, PTHrP-(1-34)NH2 induced time- and dose- dependent decreases in receptor mRNA that were preceded by pronounced desensitization (cAMP and ligand binding) of cell surface receptors. T hese effects were mimicked by (Bu)(2)cAMP and forskolin, but not by ph orbol 12-myristate 13-acetate, suggesting that both receptor mRNA down -regulation and receptor desensitization in UMR cells were mediated th rough a protein kinase-A pathway. We suggest that VSMC and UMR cells e xpress a common receptor, which is subject to cell-specific regulation . Such diversity in the PTH/PTHrP receptor regulatory mechanisms provi des a means for restricting the length and duration of the cellular re sponse to hormone in a cell/tissue-specific manner.