Endogenous parathyroid hormone-related protein functions as a neuroprotective agent.
Parathyroid hormone-related protein (PTHrP) was discovered a dozen years ago as a product of malignant tumors. It is now known that PTHrP is a paracrine factor with multiple biological functions. One such function is to relax smooth muscle by inhibiting calcium influx into the cell. In the central nervous system, PTHrP and its receptor are widely expressed in neurons in the cerebral cortex, hippocampus and cerebellum. The function of PTHrP in the CNS is not known. Previous work has shown that expression of the PTHrP gene is depolarization-dependent in cultured cerebellar granule cells and depends specifically on L-type voltage sensitive calcium channel (L-VSCC) Ca(2+) influx. PTHrP has also been found to be capable of protecting these cells against kainic acid-induced excitotoxicity. Here, we tested the idea that mice with a PTHrP-null CNS might display hypersensitivity to kainic acid excitotoxicity. We found that these mice were six-fold more sensitive than control littermate mice to kainic-acid-induced seizures as well as hippocampal c-Fos expression. PTHrP-null embryonic mixed cerebral cortical cultures were more sensitive to kainic acid than control cultures, and PTHrP addition was found to be protective against kainate toxicity in both PTHrP-null and control cultures. By whole-cell techniques, PTHrP was found to reduce L-VSCC Ca(2+) influx in cultured mouse neuroblastoma cells. We conclude that PTHrP functions as a component of a neuroprotective feedback loop that is structured around the L-type calcium channel. This loop appears to be operative in vivo as well as in vitro.
Chatterjee
Oindrila
O
Department of Internal Medicine, Yale University School of Medicine, Fitkin 100, 333 Cedar Street, P.O. Box 208020, New Haven, CT 06520-8020, USA.
Nakchbandi
Inaam A
IA
Philbrick
William M
WM
Dreyer
Barbara E
BE
Zhang
Jian Ping
JP
Kaczmarek
Leonard K
LK
Brines
Michael L
ML
Broadus
Arthur E
AE
D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D007274:Injections, Intraperitoneal; D007608:Kainic Acid / Q000494:pharmacology / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents; D044162:Parathyroid Hormone-Related Protein; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D011506:Proteins / Q000235:genetics / Q000502:physiology*
D015220:Calcium Channels; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D007770:L-Lactate Dehydrogenase; D007608:Kainic Acid