Abstract

Cyclic-ADP-ribose (cADPR) has been reported to serve as a second messenger to mobilize intracellular Ca 2+ independent of IP 3 in a variety of mammalian cells. This cADPR-mediated Ca 2+ signaling pathway importantly participates in the regulation of various cell functions. The present study determined the role of endogenous cADPR in mediating ryanodine-sensitive Ca 2+-induced Ca 2+ release (CICR) in vascular myocytes from small renal arteries and vasomotor response of these arteries. In freshly-isolated renal arterial myocytes, addition of CaCl 2 (0.01, 0.1, and 1 mM) into the Ca 2+-free bath solution produced a rapid Ca 2+ release response from the sarcoplasmic reticulum (SR), with a maximal increase of 237 ± 25 nM at 1 mM CaCl 2. This CaCl 2 response was significantly blocked by a cell-membrane permeant cADPR antagonist, 8-bromo-cADP-ribose (8-br-cADPR) (30 μM) or ryanodine (50 μM). Caffeine, a classical CICR or ryanodine receptor activator was found to stimulate the SR Ca 2+ release (Δ[Ca 2+] i: 253 ± 35 nM), which was also attenuated by 8-br-cADPR or ryanodine. Using isolated and pressurized small renal arteries bathed with Ca 2+-free solution, both CaCl 2 and caffeine-induced vasoconstrictions were significantly attenuated by either 8-br-cADPR or ryanodine. Biochemical analyses demonstrated that CaCl 2 and caffeine did not increase cADPR production in these renal arterial myocytes, but confocal microscopy showed that a dissociation of the accessory protein, FK506 binding protein 12.6 (FKBP12.6) from ryanodine receptors was induced by CaCl 2. We conclude that cADPR importantly contributes to CICR and vasomotor responses of small renal arteries through enhanced dissociation of ryanodine receptors from their accessory protein.

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