Parathyroid hormone-related peptide is produced by cultured cerebellar granule cells in response to L-type voltage-sensitive Ca2+ channel flux via a Ca2+/calmodulin-dependent kinase pathway

Abstract

Parathyroid hormone (PTH)-related peptide (PTHrP) is expressed in the adult mammalian brain, but its function is unknown. Here we show that PTHrP and the PTH/PTHrP receptor are products of cerebellar granule cells in primary culture. Granule cells maintained under depolarizing conditions (25 mM K+) make and release PTHrP. Further, PTHrP-(1-36) stimulates cAMP accumulation in granule neurons in a dose-dependent manner with half-maximal activation at ~16 nM. Granule cell PTHrP mRNA is activity-dependent, and the pathway of regulation depends absolutely on the flux of Ca2+ ions through the L-type voltage-sensitive Ca2+ channel and the Ca2+/calmodulin kinase cascade. PTHrP is therefore a neuropeptide whose regulation depends upon L- type voltage-sensitive Ca2+ channel activity, and the gene is expressed under conditions that promote granule cell survival.