Wheeler Damian G, Barrett Curtis F, Tsien Richard W
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305-5345, USA.
Neuropharmacology. 2006 Jul;51(1):27-36. doi: 10.1016/j.neuropharm.2006.02.010. Epub 2006 Apr 24.
Nicotinic acetylcholine receptors (nAChRs) are inhibited by several drugs that are commonly thought to be specific for L-type calcium channels (LTCCs). In neurons, LTCCs are activated by nicotine-induced depolarization to engage downstream signaling events; however, the role of LTCC drug interactions with nAChRs in signaling has not been examined in detail. We investigated the effects of LTCC ligands on nAChR currents and downstream signaling in rat superior cervical ganglion (SCG) neurons. We found that 10microM nicotine and 40mM K(+) both reversibly depolarize SCG neurons to -20mV, sufficient to activate LTCCs and downstream signaling, including induction of nuclear phospho-CREB (pCREB); this induction was blocked by LTCC antagonists. Interestingly, the effects of LTCC antagonists on nicotine-induced signaling to CREB are not mediated by their actions on LTCCs, but rather via inhibition of nAChRs, which prevents nicotine-induced depolarization. We show that this effect is sufficient to block pCREB induction in neurons expressing an antagonist-insensitive LTCC. Taken together, our data show that, at concentrations typically used to block LTCCs, these antagonists inhibit nAChR currents and downstream signaling. These findings serve as a caution in attributing a role for LTCCs when using these drugs experimentally or therapeutically.
烟碱型乙酰胆碱受体（nAChRs）会被几种通常被认为对L型钙通道（LTCCs）具有特异性的药物所抑制。在神经元中，LTCCs会被尼古丁诱导的去极化激活，从而引发下游信号事件；然而，LTCC药物与nAChRs在信号传导中的相互作用尚未得到详细研究。我们研究了LTCC配体对大鼠颈上神经节（SCG）神经元中nAChR电流和下游信号传导的影响。我们发现，10微摩尔的尼古丁和40毫摩尔的钾离子都会使SCG神经元可逆地去极化至-20毫伏，这足以激活LTCCs和下游信号传导，包括诱导核磷酸化CREB（pCREB）；这种诱导被LTCC拮抗剂所阻断。有趣的是，LTCC拮抗剂对尼古丁诱导的向CREB的信号传导的影响并非通过它们对LTCCs的作用介导，而是通过抑制nAChRs，从而阻止尼古丁诱导的去极化。我们表明，这种效应足以阻断表达对拮抗剂不敏感的LTCC的神经元中的pCREB诱导。综上所述，我们的数据表明，在通常用于阻断LTCCs的浓度下，这些拮抗剂会抑制nAChR电流和下游信号传导。这些发现为在实验或治疗中使用这些药物时归因于LTCCs的作用提供了警示。
