title: Discovery of a small-molecule inhibitor for kidney ADP-ribosyl cyclase: Implication for intracellular calcium signal mediated by cyclic ADP-ribose.
abstract: 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.
authors.affiliation: Department of Biochemistry, Chonbuk National University Medical School, Jeonju 561-182, Korea.
authors.forename: Tae-Sik
authors.initials: TS
authors.lastname: Nam
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Choi
authors.forename: So-Young
authors.initials: SY
authors.lastname: Rah
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Won
authors.initials: W
authors.lastname: Jang
authors.forename: Mie-Jae
authors.initials: MJ
authors.lastname: Im
authors.forename: Ho Jeong
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Uh-Hyun
authors.initials: UH
authors.lastname: Kim
mesh_terms: 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
chemical_list: D001391:Azo Compounds; D004791:Enzyme Inhibitors; D044169:Receptors, Calcium-Sensing; D036563:Cyclic ADP-Ribose; D036541:ADP-ribosyl Cyclase; C045025:4,4'-azobis(phenol)