title: Dopamine modulates inwardly rectifying potassium currents in medial prefrontal cortex pyramidal neurons.
abstract: Dopamine (DA) modulation of excitability in medial prefrontal cortex (mPFC) pyramidal neurons has attracted considerable attention because of the involvement of mPFC DA in several neuronal disorders. Here, we focused on DA modulation of inwardly rectifying K(+) current (IRKC) in pyramidal neurons acutely dissociated from rat mPFC. A Cs(+)-sensitive whole-cell IRKC was elicited by hyperpolarizing voltage steps from a holding potential of -50 mV. DA (20 microm) reduced IRKC amplitude, as did selective stimulation of DA D(1) or D(2) class receptors (D(1)Rs and D(2)Rs). D(1)Rs activate, whereas D(2)Rs inhibit, the adenylyl cyclase-cAMP-protein kinase A (PKA) signaling pathway. Suppression of IRKC by D(2)R stimulation was attributable to decreased PKA activity because similar inhibition was observed with PKA inhibitors, whereas enhancing PKA activity increased IRKC. This suggests that the DA D(1)R suppression of IRKC occurred through a PKA phosphorylation-independent process. Using outside-out patches of mPFC pyramidal neurons, which preclude involvement of cytosolic signaling molecules, we observed a Cs(+)-sensitive macroscopic IRKC that was suppressed by the membrane-permeable cyclic nucleotide Sp-cAMP but was unaffected by non-nucleotide modulators of PKA, suggesting direct interactions of the cyclic nucleotides with IRK channels. Our results indicate that DA suppresses IRKC through two mechanisms: D(1)R activation of cAMP and direct interactions of the nucleotide with IRK channels and D(2)R-mediated dephosphorylation of IRK channels. The DA modulation of IRKC indicates that ambient DA would tend to increase responsiveness to excitatory inputs when PFC neurons are near the resting membrane potential and may provide a mechanism by which DA impacts higher cognitive function.
authors.affiliation: Departments of Cellular and Molecular Pharmacology and Neuroscience, Finch University of Health Sciences/The Chicago Medical School, North Chicago, Illinois 60064, USA. yandong@stanford.edu
authors.forename: Yan
authors.initials: Y
authors.lastname: Dong
authors.forename: Donald
authors.initials: D
authors.lastname: Cooper
authors.forename: Fernando
authors.initials: F
authors.lastname: Nasif
authors.forename: Xiu-Ti
authors.initials: XT
authors.lastname: Hu
authors.forename: Francis J
authors.initials: FJ
authors.lastname: White
mesh_terms: D000818:Animals; D002469:Cell Separation; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D024661:Potassium Channels, Inwardly Rectifying; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine