D2Dopamine 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 D2receptors 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 D2receptor stimulation in enkephalin-expressing medium spiny neurons suppresses transmembrane Ca2+currents through L-type Ca2+channels, resulting in diminished excitability. This modulation is mediated by Gβγactivation 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 D2receptors in striatal medium spiny neurons, this novel signaling linkage provides a foundation for understanding how this pivotal receptor shapes striatal excitability and gene expression.