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Vasodilation by the calcium-mobilizing messenger cyclic ADP-ribose
François-Xavier Boittin1, Michelle Dipp, Nicholas P Kinnear
1Division of Biomedical Sciences, School of Biology, Bute Building, University of St Andrews, St Andrews, Fife, KY16 9TS, United Kingdom.
The Journal of Biological Chemistry
|December 18, 2002
Summary
Cyclic adenosine diphosphate-ribose (cADPR) mediates vasodilation by activating ryanodine receptors (RyRs) and calcium-activated potassium channels (BKCa). This signaling pathway contributes to blood pressure regulation via smooth muscle hyperpolarization.
Area of Science:
- Vascular smooth muscle physiology
- Molecular signaling pathways
- Cardiovascular pharmacology
Background:
- Adenylyl cyclase-coupled receptors, like beta-adrenoceptors, trigger Ca(2+) signals in artery smooth muscle.
- These Ca(2+) signals activate Ca(2+)-activated potassium (BK(Ca)) channels, leading to membrane hyperpolarization and vasodilation, potentially lowering blood pressure.
- The Ca(2+) signal originates from ryanodine receptors (RyRs) located in the sarcoplasmic reticulum near the plasma membrane.
Purpose of the Study:
- To investigate the role of cyclic adenosine diphosphate-ribose (cADPR) in mediating beta-adrenoceptor-induced vasodilation.
- To elucidate the signaling cascade involving cADPR, RyRs, and BK(Ca) channels in arterial smooth muscle.
- To determine if cADPR acts as a downstream mediator in the cAMP/PKA pathway.
Main Methods:
- Intracellular dialysis of cADPR in isolated arterial smooth muscle cells to measure cytoplasmic Ca(2+) concentration and membrane potential.
- Pharmacological blockade of RyRs (ryanodine), cADPR (8-amino-cADPR), BK(Ca) channels (iberiotoxin), and protein kinase A (H89).
- Assessment of beta-adrenoceptor-induced artery dilation in the presence of cADPR and BK(Ca) channel antagonists.
Main Results:
- Intracellular cADPR application increased proximal cytoplasmic Ca(2+) and induced membrane hyperpolarization in arterial smooth muscle cells.
- Hyperpolarization mediated by cADPR, beta-adrenoceptors, and cAMP was abolished by Ca(2+) chelation, RyR, cADPR, and BK(Ca) channel blockers.
- The PKA antagonist H89 blocked isoprenaline- and cAMP-induced hyperpolarization but not cADPR-mediated hyperpolarization, indicating cADPR acts downstream.
- Antagonists of cADPR and BK(Ca) channels inhibited beta-adrenoceptor-induced vasodilation.
Conclusions:
- cADPR is a key mediator in the vasodilation induced by adenylyl cyclase-coupled receptors.
- Arterial smooth muscle relaxation involves a cAMP-dependent, PKA-dependent increase in cADPR synthesis.
- Activated cADPR triggers Ca(2+) release via RyRs, leading to BK(Ca) channel activation, membrane hyperpolarization, and vasodilation.