How Ca_V1.2-bound verapamil blocks Ca²⁺ influx into cardiomyocyte: Atomic level views

The first clinically used antiarrhythmic, antianginal and anti-hypertensive phenylalkylamine, verapamil's cardiovascular activity is inextricably linked to its ability to antagonize Ca²⁺ overload via blocking Ca_V1.2, a cardiac L-type Ca²⁺ channel of undisputed physiological and pharmacological importance in cardiovascular disorders such as myocardial ischemia-reperfusion injury. From a structural point of view, however, the action mechanism of verapamil is still elusive. Therefore, incorporating previous findings for verapamil and Ca_V1.2, this review article puts forward two experimental data-derived and -supported 3D structure models for Ca_V1.2's α₁ subunit and its verapamil-bound form. Furthermore, this article suggests three biophysical mechanisms, namely competitive binding, steric hindrance and electrostatic repulsion, towards an atomic level understanding of how verapamil blocks the L-type Ca²⁺ current mediated by Ca_V1.2 in reality, which can be useful for the design and development of next-generation Ca²⁺ antagonists to provide safer and more effective treatment of cardiovascular diseases.