Parathyroid hormone-related protein markedly potentiates depolarization- induced catecholamine release in PC12 cells via L-type voltage-sensitive Ca2+ channels

Abstract

PTH-related protein (PTHrP) is a normal product of many excitable cells of the nervous and endocrine systems. Functions of PTHrP in these tissues are, however, currently unknown. Prior study has suggested that a relationship exists between PTHrP and the L-type voltage-sensitive Ca2+ channel (L-VSCC). For example, in cerebellar granule neurons PTHrP gene transcription is regulated by Ca2+ influx specifically through this channel. Amino-terminal PTHrP products signal via the widely expressed PTH/PTHrP receptor, which is linked to both protein kinase A and C. These second messengers are known modulators of L-VSCC conductance. To determine whether PTHrP can modulate L-VSCC function, we studied catecholamine secretion in a PC12 clone expressing the PTH/PTHrP receptor but not PTHrP. We found that PTHrP((1-36)) (100 nM) to be an ineffective secretagogue for resting cells, but its presence markedly potentiates secretion to K+ depolarization. The PTHrP-augmented catecholamine secretion depends entirely upon L-VSCC Ca2+ influx and rapidly inactivates. Similar effects were produced by (Bu)2cAMP but not by carbachol. These observations support the hypothesis that PTHrP can regulate L-VSCC conductance. In the normal adrenal medulla that expresses both PTHrP and its receptor, PTHrP may act in an autocrine/paracrine fashion to modify catecholamine secretion.