Tonic dopamine inhibition of L-type Ca2+ channel activity reduces alpha(1D) Ca2+ channel gene expression

Hormones and neurotransmitters have both short-term and long-term modulator y effects on the activity of voltage-gated Ca2+ channels. Although much is known about the signal transduction underlying short-term modulation, there is far less information on mechanisms that produce long-term effects. Here , the molecular basis of long-lasting suppression of Ca2+ channel current i n pituitary melanotropes by chronic dopamine exposure is examined. Experime nts involving in vivo and in vitro treatments with the dopaminergic drugs h aloperidol, bromocriptine, and quinpirole show that D2 receptors persistent ly decrease alpha(1D) L-type Ca2+ channel mRNA and L-type Ca2+ channel curr ent without altering channel gating properties. In contrast, another L-chan nel (alpha(1C)) mRNA and P/Q-channel (alpha(1A)) mRNA are unaffected. The d ownregulation of alpha(1D) mRNA does not require decreases in cAMP levels o r P/Q-channel activity. However, it is mimicked and occluded by inhibition of L-type channels. Thus, interruption of the positive feedback between L-t ype Ca2+ channel activity and alpha(1D) gene expression can account for the long-lasting regulation of L-current produced by chronic activation of D2 dopamine receptors.