Dopamine negatively modulates the NCA ion channels in C. elegans.
Dopamine negatively modulates the NCA ion channels in C. elegans.
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DOI：
10.1371/journal.pgen.1007032
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发表时间：
2017-10
期刊：
影响因子：
4.5
通讯作者：
Ailion M
中科院分区：
文献类型：
--
作者：
Topalidou I;Cooper K;Pereira L;Ailion M
NALCN/NCA离子通道是与电压门控钠和钙通道相关的阳离子通道。NALCN已被报道为在建立神经元静息膜电位中具有保守作用的钠泄漏通道，但其精确的细胞作用和调节尚不清楚。NALCN的秀丽隐杆线虫直系同源物NCA-1和NCA-2在前运动中间神经元中起作用以调节维持运动的运动回路活动。最近，我们发现NCA-1和NCA-2是通过异源三聚体G蛋白Gq和小GTbR Rho下游的信号转导途径激活的。通过正向遗传筛选，我们将GPCR激酶GRK-2鉴定为通过Gq-Rho-NCA途径影响信号传导的新参与者。通过结构-功能分析，我们发现GRK-2的GPCR磷酸化和膜结合结构域是其功能所必需的。遗传上位性实验表明GRK-2作用于D2样多巴胺受体DOP-3以抑制Go信号传导并正向调节NCA-1和NCA-2活性。通过细胞特异性拯救实验，我们发现GRK-2和DOP-3作用于运动前中间神经元，调节NCA通道功能。最后，我们证明，多巴胺，通过DOP-3，负调节NCA的活动。因此，本研究确定了多巴胺调节NCA通道活性的途径。多巴胺是一种神经递质，通过结合七种跨膜受体在大脑中起作用，这些受体与异源三聚体GTP结合蛋白（G蛋白）偶联。神经元G蛋白通常通过调节控制膜兴奋性的离子通道发挥作用。在这里，我们确定了一个分子级联下游的多巴胺在线虫C。包括多巴胺受体DOP-3的激活、G蛋白果阿-1的激活以及NCA-1和NCA-2离子通道的失活。我们还确定了G蛋白偶联受体激酶（GRK-2），失活多巴胺受体DOP-3，从而导致果阿-1的失活和激活的NCA通道。因此，这项研究通过G蛋白信号通路将多巴胺信号传导与NCA通道的活性联系起来。
The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels. Dopamine is a neurotransmitter that acts in the brain by binding seven transmembrane receptors that are coupled to heterotrimeric GTP-binding proteins (G proteins). Neuronal G proteins often function by modulating ion channels that control membrane excitability. Here we identify a molecular cascade downstream of dopamine in the nematode C. elegans that involves activation of the dopamine receptor DOP-3, activation of the G protein GOA-1, and inactivation of the NCA-1 and NCA-2 ion channels. We also identify a G protein-coupled receptor kinase (GRK-2) that inactivates the dopamine receptor DOP-3, thus leading to inactivation of GOA-1 and activation of the NCA channels. Thus, this study connects dopamine signaling to activity of the NCA channels through G protein signaling pathways.
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影响因子：
16.2
作者：
Brundage, L;Avery, L;Simon, MI
通讯作者：
Simon, MI
影响因子：
1.9
作者：
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影响因子：
5.3
作者：
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64.8
作者：
Funato H;Miyoshi C;Fujiyama T;Kanda T;Sato M;Wang Z;Ma J;Nakane S;Tomita J;Ikkyu A;Kakizaki M;Hotta-Hirashima N;Kanno S;Komiya H;Asano F;Honda T;Kim SJ;Harano K;Muramoto H;Yonezawa T;Mizuno S;Miyazaki S;Connor L;Kumar V;Miura I;Suzuki T;Watanabe A;Abe M;Sugiyama F;Takahashi S;Sakimura K;Hayashi Y;Liu Q;Kume K;Wakana S;Takahashi JS;Yanagisawa M
通讯作者：
Yanagisawa M
影响因子：
16.2
作者：
Ailion M;Hannemann M;Dalton S;Pappas A;Watanabe S;Hegermann J;Liu Q;Han HF;Gu M;Goulding MQ;Sasidharan N;Schuske K;Hullett P;Eimer S;Jorgensen EM
通讯作者：
Jorgensen EM