LTCCs are multimeric complexes of subunits formed by an α1 pore-forming protein associated to three auxiliary subunits (α2-δ, β, and γ). Four genes encode the pore-forming subunit (Ca_v1.1_Ca_v1.4). The primary structure, α1, is represented in the figure showing the four domains composed of six transmembrane segments. Schematic representation of the knock-in mutation in the Ca_V1.2 gene (Thr1066 to Tyr) realized by Sinnegger-Brauns and coworkers in this issue of the JCI (2) to discriminate in vivo the contributions of Ca_V1.2 and Ca_V1.3 to various physiological functions.