D2-like dopamine receptors modulate SKCa channel function in subthalamic nucleus neurons through inhibition of Cav2.2 channels

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 D-2-like dopamine receptors were studied using patch-clamp recording. In rat brain slices, D-2-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 D-2-like receptors in acutely isolated neurons reduced transient outward currents evoked by suprathreshold voltage steps. Modulation was inhibited by a D-2-like receptor antagonist and occluded by voltage-dependent Ca2+ (Ca-v) channel or small-conductance Ca2+-dependent K+ (SKCa) 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. D-2-like receptor activation reduced the conductance of Ca-v 2.2 but not Ca(v)1 channels. Modulation was mediated, in part, by direct binding of G beta gamma subunits because it was attenuated by brief depolarization. D-2 and/or D-3 dopamine receptors may mediate modulation because a D-4-selective agonist was ineffective and mRNA encoding D-2 and D-3 but not D-4 dopamine receptors was detectable. Brain slice recordings confirmed that SK Ca channel-mediated action potential afterhyperpolarization was attenuated by D-2-like dopamine receptor activation. Together, these data suggest that D-2-like dopamine receptors potently modulate the negative feedback control of firing that is mediated by the functional coupling of Ca-v 2.2 and SKCa channels in STN neurons.