Inhibition of L-Type Ca2+ Channels by Carbon Monoxide

Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 648)

Abstract

Inhibition of K+ channels in glomus cells underlies excitation of the carotid body by hypoxia. It has recently been proposed that hypoxic inhibition involves either activation of AMP activated protein kinase (AMPK) or inhibition of carbon monoxide (CO) production by heme oxygenase 2 (HO-2). In the vasculature, L-type Ca2+ channels are also O2 sensitive. Here, we have investigated the possible involvement of either AMPK or CO in the hypoxic inhibition of L-type Ca2+ channels. Using whole-cell patch clamp recordings from HEK293 cells stably expressing the human cardiac α1C2+channel subunit, we found that pre-treatment of cells with AICAR (to activate AMPK) was without effect on Ca2+ currents. CO, applied via the donor molecule CORM-2 caused reversible, voltage-independent Ca2+ channel inhibition of up to ca. 50%, whereas its inactive form (iCORM) was without significant effect. Effects of CO were prevented by the antioxidant MnTMPyP, but not by inhibition of NADPH oxidase (with either apocynin or diphenyleneiodonium), or xanthine oxidase (with allopurinol). Instead, inhibitors of complex III of the mitochondrial electron transport chain and a mitochondrial-targeted antioxidant (Mito Q), prevented the effects of CO. Our data suggest that hypoxic inhibition of L-type Ca2+ channels does not involve AMPK or CO. However, the known cardioprotective effects of HO-1 could arise from an inhibitory action of CO on L-type Ca2+ channels.

Keywords

Keywords Ca2+ channel L-type Carbon monoxide Reactive oxygen species Mitochondria Splice variant Patch clamp AMP kinase Electron transport chain 
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Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Division of Cardiovascular and Neuronal Remodelling, Leeds Institute of GeneticsHealth & Therapeutics University of LeedsLeeds LS2 9JTUK

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