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 gene s are widely expressed in the CNS and both are highly expressed in the cere bellar granule cell. We have shown previously that PTHrP gene expression in granule cells is depolarization-dependent in vitro and is regulated specif ically by Ca2+ influx via L-type voltage-sensitive calcium channels (L-VSCC s). 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 excitotoxici ty. A competitive inhibitor of PTHrP binding abrogates its neuroprotective effect. Both NTR and PTHrP decrease Ca-45(2+) influx to the same degree. Th ese findings suggest that PTHrP functions in an autocrine/paracrine neuropr otective feedback loop that can combat L-VSCC-mediated excitotoxcity. (C) 1 999 Elsevier Science Ireland Ltd. All rights reserved.