多巴胺 D1 样受体的激活通过一种 cAMP 依赖性蛋白激酶 A 非依赖的机制抑制内向整流钾电流，从而使小鼠伏隔核中的中间神经元去极化。

Dopamine D1-like receptor activation depolarizes medium spiny neurons of the mouse nucleus accumbens by inhibiting inwardly rectifying K+ currents through a cAMP-dependent protein kinase A-independent mechanism.

机构信息

Institute of Human Physiology, Medical School, Catholic University S. Cuore, Rome, Italy.

出版信息

Neuroscience. 2010 May 19;167(3):678-90. doi: 10.1016/j.neuroscience.2010.02.075. Epub 2010 Mar 6.

DOI:10.1016/j.neuroscience.2010.02.075

PMID:20211700

Abstract

Dopamine/cAMP signaling has been reported to mediate behavioral responses related to drug addiction. It also modulates the plasticity and firing properties of medium spiny neurons (MSNs) in the nucleus accumbens (NAc), although the effects of cAMP signaling on the resting membrane potential (RMP) of MSNs has not been specifically defined. In this study, activation of dopamine D1-like receptors (D1Rs) by SKF-38393 elicited membrane depolarization and inward currents in MSNs from the NAc core of 14-17 day-old mice. Similar results were obtained following stimulation of adenylyl cyclase (AC) activity with forskolin or application of exogenous cAMP. Forskolin occluded SKF-38393's effects, thus indicating that D1R action is mediated by AC/cAMP signaling. Accordingly, AC blockade by SQ22536 significantly inhibited the responses to SKF-38393. Effects elicited by D1R stimulation or increased cAMP levels were unaffected by protein kinase A (PKA) or protein kinase C (PKC) blockade and were not mimicked by the Epac agonist, 8CPT-2Me-cAMP. Responses to forskolin were also not significantly modified by cyclic nucleotide-gated (CNG) channel blockade. Forskolin-induced membrane depolarization was associated with increased membrane input resistance. Voltage-clamp experiments revealed that forskolin and SKF-38393 effects were due to inhibition of resting K(+) currents exhibiting inward rectification at hyperpolarized potentials and a reversal potential (around -90 mV) that shifted with the extracellular K(+) concentration. Forskolin and D1R agonist effects were abolished by the inward rectifier K(+) (Kir)-channel blocker, BaCl(2). Collectively, these data suggest that stimulation of postsynaptic D1Rs in MSNs of the NAc core causes membrane depolarization by inhibiting Kir currents. This effect is mediated by AC/cAMP signaling but it is independent on PKA, PKC, Epac and CNG channel activation, suggesting that it may stem from cAMP's direct interaction with Kir channels. D1R/cAMP-mediated excitatory effects may influence the generation of output signals from MSNs by facilitating their transition from the quiescent down-state to the functionally active up-state.

摘要

多巴胺/cAMP 信号转导被报道能调节与药物成瘾相关的行为反应。它还调节伏隔核（NAc）中中脑边缘多巴胺神经元（MSNs）的可塑性和放电特性，尽管 cAMP 信号转导对 MSNs 静息膜电位（RMP）的影响尚未被明确界定。在这项研究中，多巴胺 D1 样受体（D1Rs）的激活剂 SKF-38393 在来自 14-17 天大的小鼠 NAc 核心的 MSNs 中引起膜去极化和内向电流。用 forskolin 刺激腺苷酸环化酶（AC）或应用外源性 cAMP 也得到了类似的结果。 forskolin 阻断了 SKF-38393 的作用，因此表明 D1R 作用是由 AC/cAMP 信号转导介导的。相应地，AC 阻断剂 SQ22536 显著抑制了对 SKF-38393 的反应。D1R 刺激或 cAMP 水平升高引起的反应不受蛋白激酶 A（PKA）或蛋白激酶 C（PKC）阻断的影响，也不受 Epac 激动剂 8CPT-2Me-cAMP 的模拟。环核苷酸门控（CNG）通道阻断对 forskolin引起的膜去极化也没有显著影响。 forskolin 诱导的膜去极化与膜输入电阻的增加有关。电压钳实验表明， forskolin 和 SKF-38393 的作用是由于抑制了在超极化电位下表现出内向整流的静息 K(+)电流，以及一个反转电位（约-90 mV），该反转电位随细胞外 K(+)浓度而变化。内向整流钾（Kir）通道阻断剂 BaCl(2) 消除了 forskolin 和 D1R 激动剂的作用。总的来说，这些数据表明，NAc 核心 MSNs 中突触后 D1R 的刺激通过抑制 Kir 电流引起膜去极化。这种作用是由 AC/cAMP 信号转导介导的，但它独立于 PKA、PKC、Epac 和 CNG 通道的激活，表明它可能源于 cAMP 与 Kir 通道的直接相互作用。D1R/cAMP 介导的兴奋性作用可能通过促进 MSNs 从静止的向下状态过渡到功能活跃的向上状态，影响 MSNs 产生输出信号。