Calcium and the heart: exchange at the tissue, cell, and organelle levels

Cellular calcium (Ca) exchange in arterially perfused whole heart is markedly perfusion-limited. Therefore, a large fraction of exchangeable Ca recycles within the cell before exchanging with extracellular Ca. Ca enters the cell via sarcolemmal (SL) transient (T) and long-lasting (L) channels activated at more negative and less negative membrane potential, respectively. The larger L currents are controlled via phosphorylation and G protein interaction to provide Ca to induce Ca release from sarcoplasmic reticulum (SR) and for direct myofilament activation. Troponin C (TNC) binds 3 mol of Ca/mol. Only the low affinity site is responsible for activation of force and regulation of myofilament ATPase rate. This occurs through a shift in troponin I (TNI) with respect to actin induced by the TNC Ca binding. Relaxation depends on reduction of cytosolic (Ca) and occurs via 1) Ca pumping into the longitudinal SR modulated by phospholamban; 2) the recently cloned high-capacity electrogenic SL Na-Ca exchanger; and 3) the SL Ca pump under complex regulation including calmodulin control. Mitochondria transport Ca, but this transport is directed primarily to the regulation of various Ca-sensitive dehydrogenases so that oxidative metabolism can be adjusted to changes in energy demand. The regulation of Ca movements consumes about 25% of the cell's total energy output. Mitochondrial Ca exchanges with extracellular Ca most slowly (t 1/2 = 3.6 min), SR Ca quite rapidly (t 1/2's = 3 and 19 s), and an Na-Ca exchange-dependent compartment very rapidly (t 1/2 = 500 ms). After further description of Ca handling by the individual organelles, Ca movement is followed through the cell during the course of contraction, and the contribution of each organelle or compartment to overall cellular Ca exchange is defined.