Vasodilation by the calcium-mobilizing messenger cyclic ADP-ribose.

Journal article

In artery smooth muscle, adenylyl cyclase-coupled receptors such as beta-adrenoceptors evoke Ca(2+) signals, which open Ca(2+)-activated potassium (BK(Ca)) channels in the plasma membrane. Thus, blood pressure may be lowered, in part, through vasodilation due to membrane hyperpolarization. The Ca(2+) signal is evoked via ryanodine receptors (RyRs) in sarcoplasmic reticulum proximal to the plasma membrane. We show here that cyclic adenosine diphosphate-ribose (cADPR), by activating RyRs, mediates, in part, hyperpolarization and vasodilation by beta-adrenoceptors. Thus, intracellular dialysis of cADPR increased the cytoplasmic Ca(2+) concentration proximal to the plasma membrane in isolated arterial smooth muscle cells and induced a concomitant membrane hyperpolarization. Smooth muscle hyperpolarization mediated by cADPR, by beta-adrenoceptors, and by cAMP, respectively, was abolished by chelating intracellular Ca(2+) and by blocking RyRs, cADPR, and BK(Ca) channels with ryanodine, 8-amino-cADPR, and iberiotoxin, respectively. The cAMP-dependent protein kinase A antagonist N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide hydrochloride (H89) blocked hyperpolarization by isoprenaline and cAMP, respectively, but not hyperpolarization by cADPR. Thus, cADPR acts as a downstream element in this signaling cascade. Importantly, antagonists of cADPR and BK(Ca) channels, respectively, inhibited beta-adrenoreceptor-induced artery dilation. We conclude, therefore, that relaxation of arterial smooth muscle by adenylyl cyclase-coupled receptors results, in part, from a cAMP-dependent and protein kinase A-dependent increase in cADPR synthesis, and subsequent activation of sarcoplasmic reticulum Ca(2+) release via RyRs, which leads to activation of BK(Ca) channels and membrane hyperpolarization.

Authors: Boittin, F; Dipp, M; Kinnear, N; Galione, A; Evans, A

• Publication status: Published
• Journal: Journal of biological chemistry
• Volume: 278
• Issue: 11
• Pages: 9602-9608
• Publication date: 2003-03-01
• DOI: 10.1074/jbc.m204891200
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: Enzyme Inhibitors; Electrophysiology; Animals; Calcium; Vasodilator Agents; Potassium Channels; Rats; Isoproterenol; Sulfonamides; Time Factors; Cells, Cultured; Sarcoplasmic Reticulum; Cyclic ADP-Ribose; Cyclic AMP-Dependent Protein Kinases; Cyclic AMP; Peptides; Dose-Response Relationship, Drug; Arteries; Isoquinolines; Cell Membrane; Ryanodine; Ryanodine Receptor Calcium Release Channel