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

The cellular response to hypoxia is complex. Specialized oxygen chemosensit ive cells that are excitable respond to reduced O-2 by membrane depolarizat ion, altered gene expression, and neurotransmitter secretion. We have used the O-2-sensitive pheochromocytoma (PC12) cell line to investigate the cell ular response to hypoxia. Here, we present evidence that membrane depolariz ation and increased intracellular free Ca2+ are major regulatory events in these cells. Membrane depolarization is mediated by the inhibition of a slo w-inactivating voltage-dependent potassium (K) channel. Evidence from molec ular biology and patch-clamp studies indicate that the O-2-sensitive K chan nel is a member of the Kv1 family. We also reviewed findings on the regulat ion of gene expression in PC12 cells during hypoxia. An increase in intrace llular free Ca2+ is required for hypoxia-induced transcription of a number of genes including tyrosine hydroxylase (TH), the rate-limiting enzyme in t he synthesis of catecholamine neurotransmitters, and several of the immedia te early genes. We also reviewed the role of dopamine (DA) and adenosine (A DO) receptors in regulation of membrane depolarization and gene expression. (C) 1999 Elsevier Science B.V. All rights reserved.