Cardiac Intracellular Calcium Release Channels

This MiniReview is part of a thematic series on Calcium Cycling in Cardiovascular Cells, which includes the following articles: Ca2+ Release Mechanisms, Ca2+ Sparks, and Local Control of Excitation-Contraction Coupling in Normal Heart Muscle Interaction Between Ca2+ and H+ and Functional Consequences in Vascular Smooth MuscleCardiac Intracellular Calcium Release Channels: Role in Heart FailureCalcium Fluxes Involved in Control of Cardiac Myocyte ContractionC. William Balke, Guest EditorCalcium (Ca2+) ions are second messengers in numerous signaling pathways in all cell types.1 In the heart, Ca2+ regulates muscle contraction, electrical signals that determine the cardiac rhythm, and probably plays a role in controlling cell growth.2 In the last decade, elucidation of the molecular structure of the intracellular Ca2+ release channels on the sarcoplasmic reticulum (SR) and endoplasmic reticulum has led to an understanding of how these molecules regulate Ca2+ homeostasis in the heart. Consequently, the role of these channels (ryanodine receptors [RyRs] and inositol 1,4,5-trisphosphate receptors [IP3Rs]) in cardiac pathophysiology is beginning to be understood.Intracellular Ca2+ release channels form a unique class of ion channels distinguished on the basis of structure, size, and function (Figure 1⇓). RyRs and IP3Rs have large cytoplasmic domains that are involved in the regulation of the channel pore located in the carboxy terminal 10% of the channel sequence. The channels are tetrameric structures composed of 4 RyR or IP3R subunits. There are 3 forms of RyRs and 3 forms of IP3Rs (Table⇓). The RyR subunits are each ≈600 000 daltons and the IP3R subunits are each ≈300 000 daltons, yielding molecular masses for the single channels of 2.4 million and 1.2 million daltons, respectively. These channels are ≈10 times larger …