Structural basis for pore blockade of human voltage-gated calcium channel Cav1.3 by motion sickness drug cinnarizine
Xia Yao, Shuai Gao, Nieng Yan
Abstract
Voltage-gated calcium (Ca v ) channels regulate a broad range of physiological processes, such as muscle contraction, synaptic signal transduction, and hormone secretion. 1 Ca v 1.3 channels belong to the L-type (L for long-lasting current) Ca v subfamily (LTCC) and display diverse tissue distributions in brain, ear, heart, and endocrine organs. 2 Of note, Ca v 1.3 channels are predominantly expressed in cochlea inner hair cells, whose normal development and synaptic transmission are crucial for proper auditory function. herapeutic agents targeting Ca v 1.3 channels hold promises for Parkinson's disease, resistant hypertension, and hearing dysfunction. In addition to the widely prescribed dihydropyridine (DHP), phenylalkylamine (PAA), and benzothiazepine (BTZ) drugs, Ca v 1.3 channels are subject to regulation by compounds with the diphenylmethylpiperazine (DPP) core group, exemplified by cinnarizine and flunarizine (Supplementary information, Fig. he rabbit Ca v 1.1 multimeric complex purified from endogenous skeletal muscle tissues has been employed as a prototype for structural analysis of LTCC antihypertensive and antiarrhythmic agents. Here, we present the high-resolution structures of human Ca v 1.3 complex, comprising the pore-forming 1 and auxiliary 2-1 and 3 subunits. Ligand-free and cinnarizine-bound human Ca v 1.3 structures were determined at 3.0 and 3.1 resolutions, respectively.