Discovery of a small-molecule inhibitor for kidney ADP-ribosyl cyclase: Implication for intracellular calcium signal mediated by cyclic ADP-ribose

• Published in: Experimental & molecular medicine 2006-12, Vol.38 (6), p.718-726
• Main Authors: Nam, Tae-Sik, Choi, Sung Hoon, Rah, So-Young, Kim, Seon-Young, Jang, Won, Im, Mie-Jae, Kwon, Ho Jeong, Kim, Uh-Hyun
• Format: Article
• Language: English
• Subjects: ADP-ribosyl Cyclase - antagonists & inhibitors; ADP-ribosyl Cyclase - metabolism; Animals; Azo Compounds - chemistry; Azo Compounds - pharmacology; Calcium Signaling; Cell Line; Cyclic ADP-Ribose - metabolism; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Kidney - enzymology; Mice; Rats; Rats, Sprague-Dawley; Receptors, Calcium-Sensing - metabolism
• ISSN: 1226-3613; 2092-6413; 2092-6413
• DOI: 10.1038/emm.2006.84

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.