Fig 1. Ca²⁺ homeostasis and Excitation Coupling (ECC).

The ECC process is initiated when an action potential (AP) excites the myocyte cell membrane (sarcolemma) along its transverse tubules. This depolarization rapidly opens voltage-gated Na⁺ channels (mostly Na_V1.5) that further depolarize the cell membrane, allowing opening of voltage-gated Ca²⁺ channels (mostly Ca_V1.2). Inward Ca²⁺ current triggers opening of ryanodine receptor (RyR2) channels by a Ca²⁺-induced Ca²⁺ release process, resulting in coordinated release of sarcoplasmic reticulum (SR) Ca²⁺ that contributes the major portion of the myofilament-activating increase in [Ca²⁺]_i. The Ca²⁺ released from the SR binds to troponin C of the troponin-tropomyosin complex on the actin filaments in sarcomeres, facilitating formation of cross bridges between actin and myosin and myocardial contraction. Voltage-gated K⁺ channels open to allow an outward current that favors action potential repolarization, establishing conditions required for relaxation. Relaxation occurs when Ca²⁺ is taken back up into the SR through the action of the SR Ca²⁺ adenosine triphosphatase SERCA2a and is extruded from the cell by the sarcolemmal Na⁺ and Ca²⁺ exchanger (NCX). SERCA2a is constrained by phospholamban (PLN) under resting conditions.