CNGA2 Channels Mediate Adenosine-Induced Ca <sup>2+</sup> Influx in Vascular Endothelial Cells

DOI Web Site 1 Citations
  • Kwong-Tai Cheng
    From the Li Ka Shing Institute of Health Sciences and Department of Physiology, Faculty of Medicine, the Chinese University of Hong Kong, China.
  • Yuk-Ki Leung
    From the Li Ka Shing Institute of Health Sciences and Department of Physiology, Faculty of Medicine, the Chinese University of Hong Kong, China.
  • Bing Shen
    From the Li Ka Shing Institute of Health Sciences and Department of Physiology, Faculty of Medicine, the Chinese University of Hong Kong, China.
  • Yuk-Chi Kwok
    From the Li Ka Shing Institute of Health Sciences and Department of Physiology, Faculty of Medicine, the Chinese University of Hong Kong, China.
  • Ching-On Wong
    From the Li Ka Shing Institute of Health Sciences and Department of Physiology, Faculty of Medicine, the Chinese University of Hong Kong, China.
  • Hiu-Yee Kwan
    From the Li Ka Shing Institute of Health Sciences and Department of Physiology, Faculty of Medicine, the Chinese University of Hong Kong, China.
  • Yu-Bun Man
    From the Li Ka Shing Institute of Health Sciences and Department of Physiology, Faculty of Medicine, the Chinese University of Hong Kong, China.
  • Xin Ma
    From the Li Ka Shing Institute of Health Sciences and Department of Physiology, Faculty of Medicine, the Chinese University of Hong Kong, China.
  • Yu Huang
    From the Li Ka Shing Institute of Health Sciences and Department of Physiology, Faculty of Medicine, the Chinese University of Hong Kong, China.
  • Xiaoqiang Yao
    From the Li Ka Shing Institute of Health Sciences and Department of Physiology, Faculty of Medicine, the Chinese University of Hong Kong, China.

Abstract

<jats:p> <jats:bold> <jats:italic>Objectives—</jats:italic> </jats:bold> Adenosine is a cAMP-elevating vasodilator that induces both endothelium-dependent and -independent vasorelaxation. An increase in cytosolic Ca <jats:sup>2+</jats:sup> ([Ca <jats:sup>2+</jats:sup> ] <jats:sub>i</jats:sub> ) is a crucial early signal in the endothelium-dependent relaxation elicited by adenosine. This study explored the molecular identity of channels that mediate adenosine-induced Ca <jats:sup>2+</jats:sup> influx in vascular endothelial cells. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> Adenosine-induced Ca <jats:sup>2+</jats:sup> influx was markedly reduced by L- <jats:italic>cis</jats:italic> -diltiazem and LY-83583, two selective inhibitors for cyclic nucleotide-gated (CNG) channels, in H5V endothelial cells and primary cultured bovine aortic endothelial cells (BAECs). The Ca <jats:sup>2+</jats:sup> influx was also inhibited by 2 adenylyl cyclase inhibitors MDL-12330A and SQ-22536, and by 2 A <jats:sub>2B</jats:sub> receptor inhibitors MRS-1754 and 8-SPT, but not by an A <jats:sub>2A</jats:sub> receptor inhibitor SCH-58261 or a guanylyl cyclase inhibitor ODQ. Patch clamp experiments recorded an adenosine-induced current that could be inhibited by L- <jats:italic>cis</jats:italic> -diltiazem and LY-83583. A CNGA2-specific siRNA markedly decreased the Ca <jats:sup>2+</jats:sup> influx and the cation current in H5V cells. Furthermore, L- <jats:italic>cis</jats:italic> -diltiazem inhibited the endothelial Ca <jats:sup>2+</jats:sup> influx in mouse aortic strips, and it also reduced 5- <jats:italic>N</jats:italic> -ethylcarboxamidoadenosine (NECA, an A <jats:sub>2</jats:sub> adenosine receptor agonist)-induced vasorelaxation. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusion—</jats:italic> </jats:bold> CNGA2 channels play a key role in adenosine-induced endothelial Ca <jats:sup>2+</jats:sup> influx and vasorelaxation. It is likely that adenosine acts through A <jats:sub>2B</jats:sub> receptors and adenylyl cyclases to stimulate CNGA2. </jats:p>

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