D₂Dopamine Receptors in Striatal Medium Spiny Neurons Reduce L-Type Ca²⁺Currents and Excitability via a Novel PLCβ1–IP₃–Calcineurin-Signaling Cascade

Abstract

In spite of the recognition that striatal D 2 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 D 2 receptor stimulation in enkephalin-expressing medium spiny neurons suppresses transmembrane Ca 2+ currents through L-type Ca 2+ channels, resulting in diminished excitability. This modulation is mediated by G β γ activation of phospholipase C, mobilization of intracellular Ca 2+ stores, and activation of the calcium-dependent phosphatase calcineurin. In addition to providing a unifying mechanism to explain the apparently divergent effects of D 2 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.