Discovery of a small-molecule inhibitor for kidney ADP-ribosyl cyclase: Implication for intracellular calcium signal mediated by cyclic ADP-ribose.
- Author:
Tae Sik NAM
1
,
2
;
Sung Hoon CHOI
;
So Young RAH
;
Seon Young KIM
;
Won JANG
;
Mie Jae IM
;
Ho Jeong KWON
;
Uh Hyun KIM
Author Information
1. Department of Biochemistry, Chonbuk National University Medical School, Jeonju 561-182, Korea. uhkim@chonbuk.ac.kr (UHK)
2. kwonhj@yonsei.ac.kr (HJK)
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
ADP-ribosyl cyclase;
antagonists and inhibitors;
antigens, CD38;
calcium signaling;
kidney;
mesangial cells
- MeSH:
Receptors, Calcium-Sensing/metabolism;
Rats, Sprague-Dawley;
Rats;
Mice;
Kidney/*enzymology;
Humans;
Enzyme Inhibitors/chemistry/*pharmacology;
Cyclic ADP-Ribose/*metabolism;
Cell Line;
*Calcium Signaling;
Azo Compounds/chemistry/*pharmacology;
Animals;
ADP-ribosyl Cyclase/*antagonists & inhibitors/*metabolism
- From:Experimental & Molecular Medicine
2006;38(6):718-726
- CountryRepublic of Korea
- Language:English
-
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-cyclse 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.
