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L‐Type Calcium Channel Regulation of Abnormal Tyrosine Hydroxylase Expression in Cerebella of Tottering Mice

ctivity-dependent gene expression in the central nervous system depends on the proper regulation and function of voltage-dependent calcium channels (VDCCs). Calcium influx through VDCCs at the cell soma and proximal dendrites modifies a number of cellular processes via second messenger systems acting on genes and proteins with calcium-responsive properties. A role for VDCC-mediated changes in gene expression has been demonstrated in vitro. By contrast, the in vivo regulation of gene expression by VDCCs has not been extensively studied. We have used the neurological mouse mutant tottering (tg) as a model system for studying the effects of VDCC misregulation on calcium-responsive gene expression. The tg mutation alters the α1A subunit gene, which encodes P/Q-type calcium channels. 2 Recently, we have demonstrated that tg mice exhibit an upregulation of L-type calcium channels in the cerebellum. An abnormal cellular phenotype has also been identified in the cerebellum of tg mutant mice; the rate-limiting enzyme in catecholamine biosynthesis, tyrosine hydroxylase (TH), is ectopically expressed in cerebellar Purkinje cells of adult tg mice. Here, we test the hypothesis that abnormal TH expression in tg mouse cerebellar Purkinje cells is regulated by L-type calcium channels. The results suggest that the upregulation of L-type channels in tg Purkinje cells is responsible for abnormal TH gene expression. In addition, the reduction in TH mRNA in response to L-type antagonist administration demonstrates that calcium responsive gene expression is amenable to pharmacologic manipulation in vivo.