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The Journal of Neuroscience, March 24, 2004, 24(12):3077-3085; doi:10.1523/JNEUROSCI.4715-03.2004

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Cellular/Molecular
Dopamine Modulates Inwardly Rectifying Potassium Currents in Medial Prefrontal Cortex Pyramidal Neurons

Yan Dong,² Donald Cooper,¹ Fernando Nasif,¹ Xiu-Ti Hu,¹ and Francis J. White¹

Departments of ¹Cellular and Molecular Pharmacology and ²Neuroscience, Finch University of Health Sciences/The Chicago Medical School, North Chicago, Illinois 60064

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 µM) reduced IRKC amplitude, as did selective stimulation of DA D₁ or D₂ class receptors (D₁Rs and D₂Rs). D₁Rs activate, whereas D₂Rs inhibit, the adenylyl cyclase–cAMP–protein kinase A (PKA) signaling pathway. Suppression of IRKC by D₂R 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 D₁R 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: D₁R activation of cAMP and direct interactions of the nucleotide with IRK channels and D₂R-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.

View larger version (34K): [in this window] [in a new window]   Figure 8. Dopamine modulates two types of K+ currents in PFC neurons. DA modulates the VGKC and the IRKC via activation of DA D1- and D2-class receptors. Activation of D1R increases intracellular cAMP level by activation of adenylyl cyclase (AC). The intracellular cAMP may diverge into two pathways: (1) direct interaction with IRK channels and reduction of IRKC; (2) PKA-dependent phosphorylation of IRK channels and enhancement of the IRKC. Although D1R-mediated modulation of IRKC is bidirectional, the inhibitory effect predominates under normal conditions. Activation of D2R inhibits the adenylyl cyclase activity, reduces basal activity of the cAMP–PKA signal transduction pathway, and dephosphorylates IRK channels, resulting in suppression of IRKC. DA modulates the VGKC primarily through D1R, the activation of which stimulates the adenylyl cyclase–cAMP–PKA pathway and increases the phosphorylation of VGK channels, resulting in suppression of the D-type VGKC. P, Phosphorylation.

 

Key words: dopamine; D₁ receptor; potassium; inward rectifier; prefrontal cortex; drug addiction

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Received Oct 18, 2003; revised January 20, 2004; accepted February 9, 2004.

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