Calcium (Ca2) ions are second messengers in numerous sig-naling 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 than the voltage-gated Ca2 and Na channels, with Ca2 conductances on the order of 100 pS (compared with 10 pS for the voltage-gated Ca2 channels).