PARATHYROID HORMONE-RELATED PROTEIN ANTAGONIZES THE ACTION OF PARATHYROID-HORMONE ON ADULT CARDIOMYOCYTES

Ventricular cardiomyocytes have been identified as target cells for pa rathyroid hormone (PTH). A structurally related peptide hormone, parat hyroid hormone-related peptide (PTH-rP), is expressed in the heart. In the present study, it was investigated whether PTH-rP can mimic or mo dify effects of PTH on cardiomyocytes, The investigated effect was ind uction of creatine kinase (CK) activity, which is associated with card iac hypertrophy. PTH and PTH-rP have a similar secondary structure wit hin the active domain 28-34, with exception of amino acid 29. At this position the hydrophilic glutamine in the PTH molecule corresponds to hydrophobic alanine in the PTH-rP molecule. Synthetic PTH or PTH-rP pe ptides covering domain 28-34 and recombinant full-length PTH(1-84) wer e used, PTH(28-48) (100 nM) induced CK activity within 24 h (123 +/- 3 %; means +/- S.D., n = 4). PTH-rP(7-34) (1 NM to 1 mu M) failed to ind uce CK activity in cardiomyocytes, Given simultaneously, PTH-rP (1 mu M) reduced the stimulation of CK activity by PTH(1-84), PTH(1-34), and PTH(28-48) by 94 +/- 9, 79 +/- 8, and 69 +/- 14%, respectively (means +/- S.D., n = 4). In contrast, PTH rP(7-34) was sufficient to stimula te proliferation of chicken chondrocytes. Thus, PTH-rP exerts differen t effects on cardiomyocytes and classical target cells for PTH. A synt hetic hybrid peptide was synthesized, [Ala(29)]PTH(28-48), in which al anine replaced glutamine at position 29, as in the PTH-rP molecule, In contrast to PTH(28-48), this mutated peptide [Ala(29)]PTH(28-48) had no intrinsic activity but antagonized the effect of PTH(1-84) and PTH( 28-48) on cardiomyocytes. The results demonstrate that on cardiomyocyt es the effect of PTH can be antagonized by PTH-rP. This antagonism see ms due to a hydrophobic replacement at position 29.