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Volume 271, Number 45, Issue of November 8, 1996 pp. 28105-28111
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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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

(Received for publication, March 13, 1996, and in revised form, June 19, 1996)

Elizabeth H. Holt , Arthur E. Broadus ^§ and Michael L. Brines ^§

From the  Department of Cellular and Molecular Physiology and ^§ Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020

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.

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