The effects of human parathyroid hormone-related peptide on cytosolic free calcium and cAMP production in opossum kidney cell.

The effects of three synthetic amino-terminal fragments of human parathyroid hormone-related peptide (hPTHrP) on cytosolic free calcium ([Ca2+]i) mobilization and intracellular cAMP production were investigated and compared with those of human PTH(1-34) in opossum kidney (OK) cells. The mean basal [Ca2+]i in OK cells was 115 +/- 7.8 nM (mean +/- SE, n = 30). Human PTHrP(1-34), [40Tyr]hPTHrP(1-40) and hPTH(1-34) significantly (P less than 0.01) raised [Ca2+]i to 149 +/- 3, 150 +/- 5 and 148 +/- 6% of the basal value, respectively (mean +/- SE, n = 3). These three peptides showed similar dose dependency at concentrations between 10(-10) and 10(-7) M. These increases appeared to be, in part, due to mobilization from intracellular calcium stores. On the other hand, these three peptides also stimulated intracellular cAMP production in an equipotent manner in OK cells. However, both 10(-3) M dibutyryl cAMP and 10(-5) M forskolin failed to cause an increase in [Ca2+]i. Furthermore, [40Tyr]hPTHrP(3-40) neither affected the intracellular cAMP content significantly nor caused an increase in [Ca2+]i. These results indicate that hPTHrP mimics PTH by activating a dual second messenger system ([Ca2+]i and cAMP) in OK cells, and that [Ca2+]i stimulation by hPTHrP and hPTH is independent of cAMP production. Additionally, N-terminal amino acid position 1 to 2 of hPTHrP appears to play a crucial role in both [Ca2+]i stimulation and cAMP production.