Tails of the L-type Ca(2+) channel: to sense oxygen or not.

Abstract

Voltage-gated L-type Ca2+ channels are multisubunit membrane-spanning proteins that play a prominent role in a variety of Ca2+ dependent processes in cells including excitation-contraction coupling in muscle cells, excitation-secretion coupling in endocrine and neuronal cells, and gene regulation. The L-type Ca2+ channel is composed of a central pore-forming, voltage-sensing α1 subunit and auxiliary subunits including β, α2/δ, and γ.1 Multiple genes are known to encode a variety of isoforms for each subunit. Given their prominent role in the regulation of cellular processes, it is not surprising that these channels are subject to extensive regulation. A myriad of neurohumoral factors can modulate Ca2+ channel function via a variety of transmembrane receptors and signaling cascades.1 The best-studied example is β-adrenergic receptor–mediated stimulation of cardiac L-type Ca2+ channels by the cAMP/cAMP-dependent protein kinase pathway. Most of these regulatory pathways are thought to act by altering the phosphorylation status of the channel, although the molecular details of these putative phosphorylation events have not been fully resolved. But the story does not end with these channels responding only to traditional neurohormones. Recent studies have also revealed that the L-type Ca2+ channel can be modulated by hypoxia both in native vascular smooth muscle cells,2 carotid body chemoreceptor cells,3 and in recombinant systems.4 How can acute hypoxia regulate channel activity? Changes in cellular metabolism resulting from hypoxia or ischemia can modulate channel function by changing the phosphorylation status of the channel. However, there are many other manners in which channels may respond more directly and rapidly to changes in O2 levels.5 For example, a channel could contain an O2 sensing moiety such …