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D₂-Like Dopamine Receptors Modulate SK_Ca Channel Function in Subthalamic Nucleus Neurons Through Inhibition of Ca_v2.2 Channels

¹Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago Illinois; and ²Department of Biology, University of Texas at San Antonio, San Antonio, Texas

Submitted 6 September 2007; accepted in final form 13 December 2007

The activity patterns of subthalamic nucleus (STN) neurons are intimately related to motor function/dysfunction and modulated directly by dopaminergic neurons that degenerate in Parkinson's disease (PD). To understand how dopamine and dopamine depletion influence the activity of the STN, the functions/signaling pathways/substrates of D₂-like dopamine receptors were studied using patch-clamp recording. In rat brain slices, D₂-like dopamine receptor activation depolarized STN neurons, increased the frequency/irregularity of their autonomous activity, and linearized/enhanced their firing in response to current injection. Activation of D₂-like receptors in acutely isolated neurons reduced transient outward currents evoked by suprathreshold voltage steps. Modulation was inhibited by a D₂-like receptor antagonist and occluded by voltage-dependent Ca²⁺ (Ca_v) channel or small-conductance Ca²⁺-dependent K⁺ (SK_Ca) channel blockers or Ca²⁺-free media. Because Ca_v channels are targets of G_i/o-linked receptors, actions on step- and action potential waveform-evoked Ca_v channel currents were studied. D₂-like receptor activation reduced the conductance of Ca_v2.2 but not Ca_v1 channels. Modulation was mediated, in part, by direct binding of Gβ subunits because it was attenuated by brief depolarization. D₂ and/or D₃ dopamine receptors may mediate modulation because a D₄-selective agonist was ineffective and mRNA encoding D₂ and D₃ but not D₄ dopamine receptors was detectable. Brain slice recordings confirmed that SK_Ca channel-mediated action potential afterhyperpolarization was attenuated by D₂-like dopamine receptor activation. Together, these data suggest that D₂-like dopamine receptors potently modulate the negative feedback control of firing that is mediated by the functional coupling of Ca_v2.2 and SK_Ca channels in STN neurons.

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