Dopamine D2 receptor-activated Ca2+ signaling modulates voltage-sensitive sodium currents in rat nucleus accumbens neurons
Dopamine D2 receptor-activated Ca2+ signaling modulates voltage-sensitive sodium currents in rat nucleus accumbens neurons
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DOI：
10.1152/jn.00771.2004
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发表时间：
2005-03-01
影响因子：
2.5
通讯作者：
White, FJ
中科院分区：
文献类型：
--
作者：
Hu, XT;Dong, Y;White, FJ
受体介导的多巴胺(DA)对伏核(NAC)神经元兴奋性的调节作用与药物成瘾和多种脑部疾病密切相关。然而，DA调节的生理或病理分子过程的潜在机制在很大程度上仍然难以捉摸。在这里，我们证明了刺激DA D-2类受体(D2R)通过抑制环状AMP/PKA级联的紧张性活动和促进细胞内钙信号转导而增强了新分离的NAC神经元的电压敏感钠电流(VSSCs，I-Na)。D，R介导的INA增强依赖于G(I/O)蛋白的激活，并可通过直接抑制PKA来模拟。此外，通过激活肌醇1，4，5-三磷酸受体(IP(3)Rs)、阻断Ca~(2+)重摄取或添加缓冲的Ca~(2+)来增加游离[Ca~(2+)](In)。都是强化的I-Na。在这种情况下，D2R介导的I-Na增强被阻断。相反，D2R介导的IN，可被IP(3)受体抑制、游离Ca~(2+)螯合或抑制Ca~(2+)/钙调素激活的钙调神经磷酸酶(CaN)所阻断，但不能被磷脂酶C(PLC)抑制。虽然刺激M胆碱能受体(MAChRs)也能增加i-Na，但这一作用可被PLC抑制剂阻断。我们的发现表明，D(2)受体介导了NAc神经元VSSCs的增强，其中胞内游离钙离子起着关键作用。我们的结果还表明，D2R介导的紧张性PKA活性的降低可能主要通过解除对IP(3)受体的抑制而增加游离[Ca~(2+)](In)。IP3R的激活通过减少PKA诱导的磷酸化和增加CaN诱导的Na+通道去磷酸化来促进钙信号转导，进而增强VSSCs。这项研究对D(2)Rs在NAC中的复杂和动态作用提供了洞察力。
Receptor-mediated dopamine (DA) modulation of neuronal excitability in the nucleus accumbens (NAc) has been shown to be critically involved in drug addiction and a variety of brain diseases. However, the mechanisms underlying the physiological or pathological molecular process of DA modulation remain largely elusive. Here, we demonstrate that stimulation of DA D-2 class receptors (D2R) enhanced voltage-sensitive sodium currents (VSSCs, I-Na) in freshly dissociated NAc neurons via suppressing tonic activity of the cyclic AMP/PKA cascade and facilitating intracellular Ca2+ signaling. D,R-mediated INa enhancement depended on activation of G(i/o) proteins and was mimicked by direct inhibition of PKA. Furthermore, increasing free [Ca2+](in) by activating inositol 1,4,5-triphosphate receptors (IP(3)Rs), blocking Ca2+ reuptake, or adding buffered Ca2+. all enhanced I-Na. Under these circumstances, D2R-mediated I-Na enhancement was occluded. In contrast, D2R-mediated IN,, enhancement was blocked by inhibition of IP(3)Rs, chelation of free Ca2+, or inhibition of Ca2+/calmodulin-activated calcineurin (CaN), but not by inhibition of phospholipase C (PLC). Although stimulation of muscarinic cholinergic receptors (mAChRs) also increased I-Na, this action was blocked by PLC inhibitors. Our findings indicate that D(2)Rs mediate an enhancement of VSSCs in NAc neurons, in which cytosolic free Ca2+ plays a crucial role. Our results also Suggest that D2R-mediated reduction in tonic PKA activity may increase free [Ca2+](in), primarily via disinhibition of IP(3)Rs. IP3R activation then facilitates Ca2+ signaling and subsequently enhances VSSCs via decreasing PKA-induced phosphorylation and increasing CaN-induced dephosphorylation of Na+ channels. This study provides insight into the complex and dynamic role of D(2)Rs in the NAc.