T-tubule remodelling and ryanodine receptor organization modulate sodium-calcium exchange

The Na(+)/Ca(2+) exchanger (NCX) is a key regulator of intracellular Ca(2+) in cardiac myocytes, predominantly contributing to Ca(2+) removal during the diastolic relaxation process but also modulating excitation-contraction coupling. NCX is preferentially located in the T-tubules and can be close to or within the dyad, where L-type Ca(2+) channels face ryanodine receptors (RyRs), the Ca(2+) release channels of the sarcoplasmic reticulum. However, especially in larger animals, not all RyRs are in dyads or adjacent to T-tubules, and a substantial fraction of Ca(2+) release from the sarcoplasmic reticulum thus occurs at distance from NCX. This chapter deals with the functional consequences of NCX location and how NCX can modulate diastolic and systolic Ca(2+) events. The loss of T-tubules and the effects on RyR function and NCX modulation are explored, as well as quantitative measurement of local Ca(2+) gradients at the level of the dyadic space

Distribution and Regulation of L-Type Ca2+ Channels in Cardiomyocyte Microdomains

Cardiac excitation involves action potential generation by individual cells and its conduction from cell to cell through intercellular gap junctions. Excitation of the cellular membrane results in opening of the voltage-gated L-type Ca2+ channels, which allow a small amount of Ca2+ to enter the cell. This triggers the release of a much greater amount of Ca2+ from the intracellular Ca2+ store, the sarcoplasmic reticulum, and gives rise to the systolic Ca2+ transient and contraction. These processes are highly regulated by the autonomic nervous system, which ensures the acute and reliable contractile function of the heart and the short-term modulation of this function upon changes in heart rate or workload. Recently, it became evident that discrete clusters of L-type Ca2+ channels exist in the sarcolemma, where they form an interacting network with regulatory proteins and receptors. It allows the specificity, reliability, and accuracy of autonomic modulation of the excitation-contraction processes by a variety of neurohormonal pathways. Disruption in subcellular targeting of calcium channels and associated signaling pathways may contribute to the pathophysiology of a variety of cardiac diseases including heart failure and certain arrhythmias. This chapter reviews the emerging understanding of microdomain-specific distribution, functioning, regulation, and remodeling of L-type Ca2+ channels in atrial and ventricular myocytes and their contributions to the cellular signaling and cardiac pathology