Parathyroid hormone-related protein protects against kainic acid excitotoxicity in rat cerebellar granule cells by regulating L-type channel calcium flux.
The parathyroid hormone-related peptide (PTHrP) and PTH/PTHrP receptor genes are widely expressed in the CNS and both are highly expressed in the cerebellar granule cell. We have shown previously that PTHrP gene expression in granule cells is depolarization-dependent in vitro and is regulated specifically by Ca2+ influx via L-type voltage-sensitive calcium channels (L-VSCCs). Kainic acid induces long-latency excitotoxicity in granule cells via L-VSCC-mediated Ca2+ influx. Here, we show that PTHrP is just as effective as the L-VSCC blocker, nitrendipine (NTR), in preventing kainate excitotoxicity. A competitive inhibitor of PTHrP binding abrogates its neuroprotective effect. Both NTR and PTHrP decrease 45Ca2+ influx to the same degree. These findings suggest that PTHrP functions in an autocrine/paracrine neuroprotective feedback loop that can combat L-VSCC-mediated excitotoxcity.
Brines
M L
ML
Warren Laboratories, Tarrytown, NY 10591, USA.
Ling
Z
Z
Broadus
A E
AE
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D007608:Kainic Acid / Q000633:toxicity*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D009568:Nitrendipine / Q000494:pharmacology; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; C079957:parathyroid hormone-related peptide (1-36); C031617:parathyroid hormone (3-34); D009568:Nitrendipine; D007608:Kainic Acid; D002118:Calcium