title: Dopamine D2 receptor-activated Ca2+ signaling modulates voltage-sensitive sodium currents in rat nucleus accumbens neurons.
abstract: 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, I(Na)) in freshly dissociated NAc neurons via suppressing tonic activity of the cyclic AMP/PKA cascade and facilitating intracellular Ca2+ signaling. D2R-mediated I(Na) 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 (IP3Rs), 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 I(Na) enhancement was blocked by inhibition of IP3Rs, 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 D2Rs 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 IP3Rs. 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 D2Rs in the NAc.
authors.affiliation: Deptartment of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd., North Chicago, IL 60064-3095, USA. Xiu-Ti.Hu@rosalindfranklin.edu
authors.forename: Xiu-Ti
authors.initials: XT
authors.lastname: Hu
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Zhang
authors.forename: Francis J
authors.initials: FJ
authors.lastname: White
mesh_terms: D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000502:physiology*; D002614:Chelating Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004533:Egtazic Acid / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008959:Models, Neurological; D009116:Muscarine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D009714:Nucleus Accumbens / Q000166:cytology* / Q000502:physiology; D010277:Parasympathomimetics / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D037342:Pertussis Toxin / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D012457:Salicylamides / Q000494:pharmacology; D015222:Sodium Channels / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D002614:Chelating Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D018727:Muscarinic Antagonists; D010277:Parasympathomimetics; D017448:Receptors, Dopamine D2; D012457:Salicylamides; D015222:Sodium Channels; D013873:Thionucleotides; C008446:5-methylfurtrethonium; D019257:Quinpirole; C016957:adenosine-3',5'-cyclic phosphorothioate; D004533:Egtazic Acid; D001285:Atropine; D009116:Muscarine; D000242:Cyclic AMP; D037342:Pertussis Toxin; C045989:eticlopride; D002118:Calcium