D₂ dopamine receptors in striatal medium spiny neurons reduce L-type Ca²⁺ currents and excitability via a novel PLCβ1-IP₃-Calcineurin-signaling cascade

In spite of the recognition that striatal D₂ receptors are critical determinants in a variety of psychomotor disorders, the cellular mechanisms by which these receptors shape neuronal activity have remained a mystery. The studies presented here reveal that D₂ receptor stimulation in enkephalin-expressing medium spiny neurons suppresses transmembrane Ca²⁺ currents through L-type Ca²⁺ channels, resulting in diminished excitabilit. This modulation is mediated by G_βγ activation of phospholipase C, mobilization of intracellular Ca²⁺ stores, and activation of the calcium-dependent phosphatase calcineurin. In addition to providing a unifying mechanism to explain the apparently divergent effects of D₂ receptors in striatal medium spiny neurons, this novel signaling linkage provides a foundation for understanding how this pivotal receptor shapes striatal excitability and gene expression.