Induction of T-type Calcium Channel Gene Expression by Chronic Hypoxia

Abstract

Cellular responses to hypoxia can be acute or chronic. Acute responses mainly depend on oxygen-sensitive ion channels, whereas chronic responses rely on the hypoxia-inducible transcription factors (HIFs), which up-regulate the expression of enzymes, transporters, and growth factors. It is unknown whether the expression of genes coding for ion channels is also influenced by hypoxia. We report here that the alpha1H gene of T-type voltage-gated calcium channels is highly induced by lowering oxygen tension in PC12 cells. Accumulation of alpha1H mRNA in response to hypoxia is time- and dose-dependent and paralleled by an increase in the density of T-type calcium channel current recorded in patch clamped cells. HIF appears to be involved in the response to hypoxia, since cobalt chloride, desferrioxamine, and dimethyloxalylglycine, compounds that mimic HIF-regulated gene expression, replicate the hypoxic effect. Moreover, functional inhibition of HIF-2alpha protein accumulation using antisense HIF-2alpha oligonucleotides reverses the effect of hypoxia on T-type Ca2+ channel expression. Importantly, regulation by oxygen tension is specific for T-type calcium channels, since it is not observed with the L-, N-, and P/Q-channel types. These findings show for the first time that hypoxia induces an ion channel gene via a HIF-dependent mechanism and define a new role for the T-type calcium channels as regulators of cellular excitability and calcium influx under chronic hypoxia.