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.
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 approximately 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.
Holt
E H
EH
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA.
Broadus
A E
AE
Brines
M L
ML
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D005260:Female; D044162:Parathyroid Hormone-Related Protein; D011188:Potassium / Q000378:metabolism; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000378:metabolism; D014701:Veratridine / Q000494:pharmacology
D002118:Calcium; D015220:Calcium Channels; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D044162:Parathyroid Hormone-Related Protein; D011188:Potassium; D011494:Protein Kinases; D012333:RNA, Messenger; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D014701:Veratridine