title: T-Type Ca2+ Channel Regulation by CO: A Mechanism for Control of Cell Proliferation.
abstract: T-type Ca(2+) channels regulate proliferation in a number of tissue types, including vascular smooth muscle and various cancers. In such tissues, up-regulation of the inducible enzyme heme oxygenase-1 (HO-1) is often observed, and hypoxia is a key factor in its induction. HO-1 degrades heme to generate carbon monoxide (CO) along with Fe(2+) and biliverdin. Since CO is increasingly recognized as a regulator of ion channels (Peers et al. 2015), we have explored the possibility that it may regulate proliferation via modulation of T-type Ca(2+) channels.Whole-cell patch-clamp recordings revealed that CO (applied as the dissolved gas or via CORM donors) inhibited all 3 isoforms of T-type Ca(2+) channels (Cav3.1-3.3) when expressed in HEK293 cells with similar IC(50) values, and induction of HO-1 expression also suppressed T-type currents (Boycott et al. 2013). CO/HO-1 induction also suppressed the elevated basal [Ca(2+) ](i) in cells expressing these channels and reduced their proliferative rate to levels seen in non-transfected control cells (Duckles et al. 2015).Proliferation of vascular smooth muscle cells (both A7r5 and human saphenous vein cells) was also suppressed either by T-type Ca(2+) channel inhibitors (mibefradil and NNC 55-0396), HO-1 induction or application of CO. Effects of these blockers and CO were non additive. Although L-type Ca(2+) channels were also sensitive to CO (Scragg et al. 2008), they did not influence proliferation. Our data suggest that HO-1 acts to control proliferation via CO modulation of T-type Ca(2+) channels.
authors: Department of Cardiovascular Science, Medical School, University of Sheffield, Sheffield, S10 2RX, UK.
authors: Hayley
authors: H
authors: Duckles
authors: Moza M
authors: MM
authors: Al-Owais
authors: Jacobo
authors: J
authors: Elies
authors: Emily
authors: E
authors: Johnson
authors: Hannah E
authors: HE
authors: Boycott
authors: Mark L
authors: ML
authors: Dallas
authors: Karen E
authors: KE
authors: Porter
authors: John P
authors: JP
authors: Boyle
authors: Jason L
authors: JL
authors: Scragg
authors: Chris
authors: C
authors: Peers
mesh_terms: D002118:Calcium / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000032:analysis / Q000502:physiology*; D002248:Carbon Monoxide / Q000494:pharmacology*; D049109:Cell Proliferation; D057809:HEK293 Cells; D051547:Heme Oxygenase-1 / Q000502:physiology; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000502:physiology
chemical_list: C479952:CACNA1H protein, human; D020747:Calcium Channels, T-Type; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D002118:Calcium