Excitation-contraction coupling (ECC) converts electrical stimuli to mechanical responses. Herein we provide a concise summary of the most updated insights on, and nomenclature of, the main actors involved in cardiac ECC, posing the basis for pharmacologic interventions in heart failure (HF) and arrhythmias. Recently introduced therapeutic strategies targeting myocardial ECC are appraised as well, specifying their molecular mechanism of action. Excitation-contraction coupling starts with the entry of Ca2+ into the cardiomyocyte through the L-type Ca2+ channels (LTCC, also known as dihydropyridine channel); this step triggers Ca2+-induced Ca2+-release from the sarcoplasmic reticulum (SR) by activating type 2 ryanodine receptor Ca2+ release channel (RyR2). 1 Ca2+-releasing units consisting of closely (∼ 15 nm) approximated LTCCs (on T-tubules, which are invaginations of the sarcolemma with a diameter of∼ 200 nm that form a highly branched network) and RyRs (on the SR) are known as dyadic clefts or dyads; within each dyad,∼ 25 LTCCs and∼ 100 RyRs are closely associated (∼ 1: 4 ratio). Junctophilin-2 is a membrane-binding protein that is responsible for the localization of LTCCs in close proximity to RyR2. Mutations in the joining region of Junctophilin-2 cause T-tubule remodeling and dyad loss with subsequent asynchronous Ca2+-release after β-adrenergic stimulation. 2

LTCC contains the α1 subunit, a tetramer of four six-transmembrane domains forming the pore, and auxiliary subunits (α2δ, β, γ). The α1 subunit, known as Ca2+-voltage-gated channel subunit α1 (CaV1), has four isoforms: α1S (CaV1. 1), α1C (CaV1. 2), α1D (CaV1. 3), and α1F (CaV1. 3). Two groups of Ca2+-voltage-gated channels complete the family: CaV2 (P-type, N-type, R-type), and CaV3 (T-type). RyR2, a tetrameric intracellular Ca2+-release channel located on the SR, can be modulated by post-translational modifications and by interactions with a number of other proteins, including