Autoinhibition of transmitter release from PC12 cells and sympathetic neurons through a P2Y12 receptor-mediated inhibition of voltage-gated Ca2+ channels

被引:34
作者
Lechner, SG [1 ]
Dorostkar, MM [1 ]
Mayer, M [1 ]
Edelbauer, H [1 ]
Pankevych, H [1 ]
Boehm, S [1 ]
机构
[1] Med Univ Vienna, Inst Pharmacol, A-1090 Vienna, Austria
关键词
Ca2+ current; cyclic AMP; noradrenaline release; rat;
D O I
10.1111/j.1460-9568.2004.03760.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Although feedback inhibition of noradrenaline release by coreleased nucleotides is a well known phenomenon, it remained unclear which P2 receptor subtypes and associated signalling cascades may be involved. In the rat pheochromocytoma cell line PC12, 2-methylthio-ADP reduced noradrenaline release triggered by K+ depolarization more potently than ADP and ATP, whereas UDP or UTP failed to do so. The inhibition by ADP was abolished by pertussis toxin and antagonized by reactive blue 2, 2-methylthio-AMP, and AR-C69931MX, but not by suramin. AR-C69931MX acted as a competitive antagonist with an apparent affinity of 2 nM, but did not alter noradrenaline release, when PC12 cells were continuously superfused. However, when the superfusion was halted during K+ depolarization, release was significantly reduced and this inhibition was attenuated by AR-C69931MX, thus revealing ongoing autoinhibition. Rises in cellular cyclic AMP did not alter depolarization-evoked release nor its reduction by ADP, even though the nucleotide did inhibit cyclic AMP accumulation. ADP and the direct Ca2+ channel blocker Cd2+ inhibited voltage-activated Ca2+ currents, but not ATP-induced currents, and both agents reduced K+-evoked, but not ATP-evoked, release. Hence, if voltage-gated Ca2+ channels do not contribute to stimulation-evoked release, ADP fails to exert its inhibitory action. In primary cultures of rat sympathetic neurons, ADP also reduced Ca2+ currents and K+-evoked noradrenaline release, and AR-C69931MX acted again as competitive antagonist with an apparent affinity of 3 nM. These results show that P2Y(12) receptors mediate an autoinhibition of transmitter release from PC12 cells and sympathetic neurons through an inhibition of voltage-gated Ca2+ channels.
引用
收藏
页码:2917 / 2928
页数:12
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