Regulation of gene expression and secretory functions in oxygen-sensing pheochromocytoma cells

Abstract

The cellular response to hypoxia is complex. Specialized oxygen chemosensitive cells that are excitable respond to reduced O 2 by membrane depolarization, altered gene expression, and neurotransmitter secretion. We have used the O 2-sensitive pheochromocytoma (PC12) cell line to investigate the cellular response to hypoxia. Here, we present evidence that membrane depolarization and increased intracellular free Ca 2+ are major regulatory events in these cells. Membrane depolarization is mediated by the inhibition of a slow-inactivating voltage-dependent potassium (K) channel. Evidence from molecular biology and patch-clamp studies indicate that the O 2-sensitive K channel is a member of the Kv1 family. We also reviewed findings on the regulation of gene expression in PC12 cells during hypoxia. An increase in intracellular free Ca 2+ is required for hypoxia-induced transcription of a number of genes including tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamine neurotransmitters, and several of the immediate early genes. We also reviewed the role of dopamine (DA) and adenosine (ADO) receptors in regulation of membrane depolarization and gene expression.