G protein-mediated inhibition of Cav3.2 T-type channels revisited.

T-type calcium channels are important modulators of both membrane potential and intracellular Ca(2+) concentration, allowing them to play key roles in such diverse processes as aldosterone production from adrenal glomerulosa cells to boosting pain signals in nociceptors. In both these examples, the Ca(v)3.2 isoform mediates Ca(2+) influx. This isoform is also of particular interest because mutations in its gene (CACNA1H) that enhance channel activity have been associated with idiopathic generalized epilepsies, whereas mutations that disrupt its activity have been associated with autism spectrum disorders. Block of T-channel activity has been proposed to contribute to the therapeutic usefulness of a wide variety of drugs, such as antihypertensives, antipsychotics, and antidepressants. Recent evidence strongly supports the hypothesis that block of Ca(v)3.2 channels might be useful in the treatment of neuropathic pain. Therefore, it is of particular interest that Ca(v)3.2 channels are exquisitely regulated by G protein-coupled receptors and various downstream effectors. This Perspective summarizes recent findings (p. 202) on this regulation and the novel pathways specifically activated by either neurokinin I, corticotropin-releasing factor receptor 1, or dopamine D(1) receptors.