NAADP⁺ is an agonist of the human P2Y₁₁ purinergic receptor

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• 作者：Iliana Moreschi ; Santina Bruzzone ; Nicoletta Bodrato ; Cesare Usai ; Lucrezia Guida ; Robert A. Nicholas ; Matthias U. Kassack ; Elena Zocchi ; Antonio De Flora
• 关键词：NAADP⁺ ; P2Y₁₁ receptors ; IP₃ ; cADPR ; Intracellular calcium concentration
• 刊名：Cell Calcium
• 出版年：2008
• 出版时间：April 2008
• 年：2008
• 卷：43
• 期：4
• 页码：344-355
• 全文大小：680 K

文摘

Nicotinic acid adenine dinucleotide phosphate (NAADP⁺) is an intracellular second messenger releasing Ca²⁺ from intracellular stores in different cell types. In addition, it is also active in triggering [Ca²⁺]_i increase when applied extracellularly and various underlying mechanisms have been proposed. Here, we used hP2Y₁₁-transfected 1321N1 astrocytoma cells to unequivocally establish whether extracellular NAADP⁺ is an agonist of the P2Y₁₁ receptor, as previously reported for β-NAD⁺ [I. Moreschi, S. Bruzzone, R.A. Nicholas, et al., Extracellular NAD⁺ is an agonist of the human P2Y11 purinergic receptor in human granulocytes, J. Biol. Chem. 281 (2006) 31419–31429]. Extracellular NAADP⁺ triggered a concentration-dependent two-step elevation of [Ca²⁺]_i in 1321N1-hP2Y₁₁ cells, but not in wild-type 1321N1 cells, secondary to the intracellular production of IP₃, cAMP and cyclic ADP-ribose (cADPR). Specifically, the transient [Ca²⁺]_i rise proved to be related to IP₃ overproduction and to consequent Ca²⁺ mobilization, while the sustained [Ca²⁺]_i elevation was caused by the cAMP/ADP-ribosyl cyclase (ADPRC)/cADPR signalling cascade and by influx of extracellular Ca²⁺. In human granulocytes, endogenous P2Y₁₁ proved to be responsible for the NAADP⁺-induced cell activation (as demonstrated by the use of NF157, a selective and potent inhibitor of P2Y₁₁), unveiling a role of NAADP⁺ as a pro-inflammatory cytokine. In conclusion, we provide unequivocal evidence for the activation of a member of the P2Y receptor subfamily by NAADP⁺.