Amplification of depolarization-induced and ryanodine-sensitive cytosolic Ca2+ elevation by synthetic carbocyclic analogs of cyclic ADP-ribose and their antagonistic effects in NG108-15 neuronal cells |
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Authors: | Hashii Minako Shuto Satoshi Fukuoka Masayoshi Kudoh Takashi Matsuda Akira Higashida Haruhiro |
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Institution: | Department of Biophysical Genetics, Kanazawa University Graduate School of Medicine, Kanazawa, Japan. mhashii@med.kanazawa-u.ac.jp |
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Abstract: | We synthesized analogs modified in the ribose unit (ribose linked to N1 of adenine) of cyclic ADP-ribose (cADPR), a Ca2+-mobilizing second messenger. The biological activities of these analogs were determined in NG108-15 neuroblastoma x glioma hybrid cells that were pre-loaded with fura-2 acetoxymethylester and subjected to whole-cell patch-clamp. Application of the hydrolysis-resistant cyclic ADP-carbocyclic-ribose (cADPcR) through patch pipettes potentiated elevation of the cytoplasmic free Ca2+ concentration (Ca2+]i) at the depolarized membrane potential. The increase in Ca2+]i evoked upon sustained membrane depolarization was significantly larger in cADPcR-infused cells than in non-infused cells and its degree was equivalent to or significantly greater than that induced by cADPR or beta-NAD+. 8-Chloro-cADPcR and two inosine congeners (cyclic IDP-carbocyclic-ribose and 8-bromo-cyclic IDP-carbocyclic-ribose) did not induce effects similar to those of cADPcR or cADPR. Instead, 8-chloro-cADPcR together with cADPR or cADPcR caused inhibition of the depolarization-induced Ca2+]i increase as compared with either cADPR or cADPcR alone. These results demonstrated that our cADPR analogs have agonistic or antagonistic effects on the depolarization-induced Ca2+]i increase and suggested the presence of functional reciprocal coupling between ryanodine receptors and voltage-activated Ca2+ channels via cADPR in mammalian neuronal cells. |
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Keywords: | cyclic ADP‐ribose cytoplasmic free Ca2+ concentration β‐nicotinamide adenine dinucleotide neuroblastoma NG108‐15 cells ryanodine receptor |
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