Advances in the understanding of excitation-contraction coupling: the pulsing quest for drugs against heart failure and arrhythmias
Urna Kansakar, Fahimeh Varzideh, Stanislovas S. Jankauskas, Jessica Gambardella, Bruno Trimarco, Gaetano Santulli
Abstract
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...