Signaling Modulates Voltage-Sensitive Sodium Currents in Rat Nucleus Accumbens Neurons

Hu, Xiu-Ti, Yan Dong, Xu-Feng Zhang, and Francis J. White. Dopamine D2 receptor-activated Ca 2 signaling modulates voltagesensitive sodium currents in rat nucleus accumbens neurons. J Neurophysiol 93: 1406–1417, 2005 doi:10.1152/jn.00771.2004. 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 D2 class receptors (D2R) enhanced voltage-sensitive sodium currents (VSSCs, INa) in freshly dissociated NAc neurons via suppressing tonic activity of the cyclic AMP/PKA cascade and facilitating intracellular Ca signaling. D2R-mediated INa enhancement depended on activation of Gi/o proteins and was mimicked by direct inhibition of PKA. Furthermore, increasing free [Ca ]in by activating inositol 1,4,5-triphosphate receptors (IP3Rs), blocking Ca reuptake, or adding buffered Ca , all enhanced INa. Under these circumstances, D2R-mediated INa enhancement was occluded. In contrast, D2R-mediated INa enhancement was blocked by inhibition of IP3Rs, chelation of free Ca 2 , or inhibition of Ca / calmodulin-activated calcineurin (CaN), but not by inhibition of phospholipase C (PLC). Although stimulation of muscarinic cholinergic receptors (mAChRs) also increased INa, this action was blocked by PLC inhibitors. Our findings indicate that D2Rs mediate an enhancement of VSSCs in NAc neurons, in which cytosolic free Ca plays a crucial role. Our results also suggest that D2R-mediated reduction in tonic PKA activity may increase free [Ca ]in, primarily via disinhibition of IP3Rs. IP3R activation then facilitates Ca 2