D-2 dopamine receptors in striatal medium spiny neurons reduce L-type Ca2+currents and excitability via a novel PLC beta 1-IP3-calcineurin-signalingcascade

In spite of the recognition that striatal D-2 receptors are critical determ inants in a variety of psychomotor disorders, the cellular mechanisms by wh ich these receptors shape neuronal activity have remained a mystery. The st udies presented here reveal that D-2 receptor stimulation in enkephalin-exp ressing medium spiny neurons suppresses transmembrane Ca2+ currents through L-type Ca2+ channels, resulting in diminished excitability. This modulatio n is mediated by G(beta gamma) activation of phospholipase C, mobilization of intracellular Ca2+ stores, and activation of the calcium-dependent phosp hatase calcineurin. In addition to providing a unifying mechanism to explai n the apparently divergent effects of D-2 receptors in striatal medium spin y neurons, this novel signaling linkage provides a foundation for understan ding how this pivotal receptor shapes striatal excitability and gene expres sion.