NAADP receptors mediate calcium signaling stimulated by endothelin-1 and norepinephrine in renal afferent arterioles.
The enzyme ADP-ribosyl (ADPR) cyclase plays a significant role in mediating increases in renal afferent arteriolar cytosolic calcium concentration ([Ca(2+)](i)) in vitro and renal vasoconstriction in vivo. ADPR cyclase produces cyclic ADP ribose, a second messenger that contributes importantly to ryanodine receptor-mediated Ca(2+) mobilization in renal vascular responses to several vasoconstrictors. Recent studies in nonrenal vascular smooth muscle cells (VSMC) have shown that nicotinic acid adenine dinucleotide phosphate (NAADP), another second messenger generated by ADPR cyclase, may contribute to Ca(2+) signaling. We tested the hypothesis that a Ca(2+) signaling pathway involving NAADP receptors participates in afferent arteriolar [Ca(2+)](i) responses to the G protein-coupled receptor agonists endothelin-1 (ET-1) and norepinephrine (NE). To test this, we isolated rat renal afferent arterioles and measured [Ca(2+)](I) using fura-2 fluorescence. We compared peak [Ca(2+)](i) increases stimulated by ET-1 and NE in the presence and absence of inhibitors of acidic organelle-dependent Ca(2+) signaling and NAADP receptors. Vacuolar H(+)-ATPase inhibitors bafilomycin A1 and concanamycin A, disruptors of pH and Ca(2+) stores of lysosomes and other acidic organelles, individually antagonized [Ca(2+)](i) responses to ET-1 and NE by 40-50% (P < 0.05). The recently discovered NAADP receptor inhibitor Ned-19 attenuated [Ca(2+)](i) responses to ET-1 or NE by 60-70% (P < 0.05). We conclude that NAADP receptors contribute to both ET-1- and NE-induced [Ca(2+)](i) responses in afferent arterioles, an effect likely dependent on acidic vesicle, possibly involving lysosome, signaling in VSMC in the renal microcirculation.
Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Tiffany L
TL
Thai
Grant C
GC
Churchill
William J
WJ
Arendshorst
D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D000818:Animals; D001160:Arterioles / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002243:Carbolines / Q000494:pharmacology; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply*; D018942:Macrolides / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism
C539827:1-(3-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido(3,4-b)indole-3-carboxylic acid; D002243:Carbolines; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D018942:Macrolides; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D009249:NADP; C024376:NAADP; C036978:concanamycin A; C040929:bafilomycin A1; D036541:ADP-ribosyl Cyclase; D025262:Vacuolar Proton-Translocating ATPases; D009638:Norepinephrine