Regulation of ryanodine receptors from skeletal and cardiac muscle during rest and excitation

In muscle, intracellular calcium concentration, hence skeletal muscle force and cardiac output, is regulated by uptake and release of calcium from the sarcoplasmic reticulum (SR). The ryanodine receptor (RyR) forms the calcium release channel in the SR. Calcium release through RyRs is modulated by a wide variety of endogenous molecules, including small diffusible ligands such as ATP, Ca2+ and Mg2+. The regulation of RyR channels by ATP, Ca2+ and Mg2+ is a complex interplay of several regulatory mechanisms, which are still being unravelled. Consequently, it is not clearly known how RyRs are regulated in resting muscle and during contraction. The present paper reviews factors controlling the activity of RyRs in skeletal and cardiac muscle with an emphasis on mechanistic insights derived from single channel recording methods. In addition, the nature of dihydropyridine receptor (DHPR) control of RyRs in skeletal muscle derived from experiments with peptide fragments of the DHPR II-III loop is reviewed. Finally, recent experiments on coupled RyRs in lipid bilayers and their potential for resolving the elusive mechanisms controlling calcium release during cardiac contraction are discussed.