Vasodilation by the Calcium-mobilizing Messenger Cyclic ADP-ribose

Abstract

In artery smooth muscle, adenylyl cyclase-coupled receptors such as ␤-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 ␤-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 ␤-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 ␤-adrenoreceptorinduced 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.

Two-pore channel 1 interacts with citron kinase, regulating completion of cytokinesis

“…3,4,7 In plants, studies of Ca 2C release in Arabidopsis identified AtTPC1 as a channel 8 that mediates the slow vacuolar current, 9 regulating germination and stomatal movement. 10 TPCs have been shown to regulate differentiation, 11 smooth muscle contraction 12 and endothelial cell activation, 13 consistent with previous studies implicating nicotinic acid adenine dinucleotide phosphate (NAADP)-induced Ca 2C release in these events, [14][15][16] and supported by several overexpression, knockdown and knockout models. 3,4,6,17 Regulation and affinity of TPC ion channels is a contentious issue.…”

Oxytocin-induced elevation of ADP-ribosyl cyclase activity, cyclic ADP-riboseor Ca2+ concentrations is involved in autoregulation of oxytocin secretionin the hypothalamus and posterior pituitary in male mice

“…Intracellular cADPR concentrations are known to be regulated in many different ways: in one such mechanism, ADP-ribosyl cyclase or CD38 seems to be coupled directly with neurotransmitter or hormone receptors such as muscarinic acetylcholine or metabotropic glutamate receptors via different G proteins on the membrane surface (Higashida et al, 1997(Higashida et al, , 1999(Higashida et al, , 2007; or phosphorylation downstream of the G-protein-coupled receptor signaling pathway (Boittin et al, 2003;Sternfeld et al, 2003). Specifically, the activation of ADP-ribosyl cyclase or CD38 by cyclic GMP-or cyclic AMP-dependent protein kinases has been reported in Aplysia californica (Graeff et al, 1998), LAK cells (Rah et al, 2005) and artery smooth muscle cells (Boittin et al, 2003). However, there have been no previous reports regarding the mechanisms by which ADP-ribosyl cyclase and CD38 are activated after OT receptor stimulation in the hypothalamus, leading to secretion of OT.…”

Association of CD38 with Nonmuscle Myosin Heavy Chain IIA and Lck Is Essential for the Internalization and Activation of CD38

“…Mounting evidence indicates that cADPR synthesis by ADP-ribosyl cyclases is stimulated through cell-surface heterotrimeric G-protein-coupled receptor signaling. The receptors involved in ADP-ribosyl cyclase activation include the ␤-adrenergic (11,12), angiotensin II (13), and muscarinic (14) receptors. Activation of ADP-ribosyl cyclase/CD38 by cGMP has been reported (15,16), and cAMP-dependent activation of the enzyme has also been observed in artery smooth muscle cells (12) and cardiomyocytes (17).…”

“…The receptors involved in ADP-ribosyl cyclase activation include the ␤-adrenergic (11,12), angiotensin II (13), and muscarinic (14) receptors. Activation of ADP-ribosyl cyclase/CD38 by cGMP has been reported (15,16), and cAMP-dependent activation of the enzyme has also been observed in artery smooth muscle cells (12) and cardiomyocytes (17). However, the molecular mechanism of ADPribosyl cyclase/CD38 activation has not been completely elucidated.…”