Paradoxical role of T-type calcium channels in coronary smooth muscle. Mol Interv

Calcium influx via voltage-gated channels plays important roles in muscle excitation-contraction coupling, hormone and neurotransmit-ter stimulus-secretion coupling, regulation of gene transcription, and neuronal firing. To fulfill these diverse roles, mammals have evolved ten genes encoding voltage-gated calcium channels (Cav channels) (Figure 1). These channels also serve as important drug targets, with most therapeutically useful calcium-channel blockers targeting L-type channels, such as Cav1.2, found on cardiac or smooth muscle. These drugs (e.g., amlodipine) are useful in the treatment of high blood pressure because they block Ca2+ influx via L-type channels into smooth muscle cells (SMC), which results in relaxation. SMCs also express T-type calcium currents (1). The develop-ment and characterization of mibefradil (also termed Ro 40-5967), a novel antihypertensive drug with modest selectivity for T-type channels (2), supported the hypothesis that blocking T-type chan