Discovery of a small-molecule inhibitor for kidney ADP-ribosyl cyclase: Implication for intracellular calcium signal mediated by cyclic ADP-ribose.
ADP-ribosyl cyclase (ADPR-cyclase) produces a Ca2+-mobilizing second messenger, cyclic ADP- ribose (cADPR), from beta-NAD+. A prototype of mammalian ADPR-cyclases is a lymphocyte antigen CD38. Accumulating evidence indicates that ADPR-cyclases other than CD38 are expressed in various cells and organs. In this study, we discovered a small molecule inhibitor of kidney ADPR-cyclase. This compound inhibited kidney ADPR-cyclase activity but not CD38, spleen, heart or brain ADPR-cyclase activity in vitro. Characterization of the compound in a cell-based system revealed that an extracellular calcium-sensing receptor (CaSR)- mediated cADPR production and a later long-lasting increase in intracellular Ca2+ concentration ([Ca2+]i) in mouse mesangial cells were inhibited by the pre-treatment with this compound. In contrast, the compound did not block CD3/TCR-induced cADPR production and the increase of [Ca2+]i in Jurkat T cells, which express CD38 exclusively. The long-lasting Ca2+ signal generated by both receptors was inhibited by pre-treatment with an antagonistic cADPR derivative, 8-Br-cADPR, indicating that the Ca2+ signal is mediated by the ADPR-cyclase metabolite, cADPR. Moreover, among structurally similar compounds tested, the compound inhibited most potently the cADPR production and Ca2+ signal induced by CaSR. These findings provide evidence for existence of a distinct ADPR-cyclase in the kidney and basis for the development of tissue specific inhibitors.
Nam
Tae-Sik
TS
Department of Biochemistry, Chonbuk National University Medical School, Jeonju 561-182, Korea.
Choi
Sung Hoon
SH
Rah
So-Young
SY
Kim
Seon-Young
SY
Jang
Won
W
Im
Mie-Jae
MJ
Kwon
Ho Jeong
HJ
Kim
Uh-Hyun
UH
D036541:ADP-ribosyl Cyclase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D001391:Azo Compounds / Q000737:chemistry / Q000494:pharmacology*; D020013:Calcium Signaling; D002460:Cell Line; D036563:Cyclic ADP-Ribose / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007668:Kidney / Q000201:enzymology*; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000378:metabolism
D001391:Azo Compounds; D004791:Enzyme Inhibitors; D044169:Receptors, Calcium-Sensing; D036563:Cyclic ADP-Ribose; D036541:ADP-ribosyl Cyclase; C045025:4,4'-azobis(phenol)