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T-Type Ca2+ Channel Regulation by CO: A Mechanism for Control of Cell Proliferation

  • Hayley Duckles
  • Moza M. Al-Owais
  • Jacobo Elies
  • Emily Johnson
  • Hannah E. Boycott
  • Mark L. Dallas
  • Karen E. Porter
  • John P. Boyle
  • Jason L. Scragg
  • Chris PeersEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 860)

Abstract

T-type Ca2+ 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 Fe2+ 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 Ca2+ 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 Ca2+ channels (Cav3.1-3.3) when expressed in HEK293 cells with similar IC50 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 [Ca2+ ]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 Ca2+ 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 Ca2+ 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 Ca2+ channels.

Keywords

Heme oxygenase Carbon monoxide T-type Ca2+ channel Smooth muscle Vascular disease Proliferation 

Notes

Acknowledgements

This work was supported by the British Heart Foundation.

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Hayley Duckles
    • 1
  • Moza M. Al-Owais
    • 2
  • Jacobo Elies
    • 2
  • Emily Johnson
    • 2
  • Hannah E. Boycott
    • 3
  • Mark L. Dallas
    • 4
  • Karen E. Porter
    • 2
  • John P. Boyle
    • 2
  • Jason L. Scragg
    • 2
  • Chris Peers
    • 5
    Email author
  1. 1.Department of Cardiovascular Science, Medical SchoolUniversity of SheffieldSheffieldUK
  2. 2.Division of Cardiovascular and Diabetes Research, LIGHT, Faculty of Medicine and HealthUniversity of LeedsLeedsUK
  3. 3.Life Sciences CentreUniversity of British ColumbiaVancouverCanada
  4. 4.School of PharmacyUniversity of ReadingReadingUK
  5. 5.Leeds Institute of Cardiovascular and Metabolic Medicine, Faculty of Medicine and HealthUniversity of LeedsLeedsUK

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