SPST

Abstract: 

Voltage-gated calcium (Ca_v) channels are important membrane proteins that mediate calcium influx upon action potential. They are involved in a variety of physiological processes, such as muscle contraction, hormone secretion, synaptic transmission and gene expression. Malfunction of Ca_v channels are associated with many neurological and cardiovascular diseases. Therefore, Ca_v channels are very important drug targets. In fact, several clinical drugs targeted on Ca_v1 channels have already been widely used for treatment of hypertension. Ca_v1.1 was the first identified among the 10 Ca_v channels in mammals and it plays an essential role during excitation-contraction (E-C) coupling duringskeletal muscle contraction. In the past few years, we were focusing on the structural investigation on Ca_v1.1. We sought an innovative strategy to purify the large protein complex form endogenous tissue. Using single particle cryo-EM, we solved the structure of Ca_v1.1, which was the first high resolution structure of a eukaryotic Ca_v channel. The structure helped explaining the subunits assembly, ion selectivity, electro-mechanical coupling of Ca_v channels. By combining the study on another ion channel RyR1, we also proposed a working model for EC-coupling in skeletal muscle. Recently, we also solved the structures of Ca_v1.1 in complex with multiple clinical drugs. These structures elucidate the structural basis for specific drug recognition and will provide important framework for future drug developments.