Putative roles of type 3 ryanodine receptor isoforms (RyR3)

Ca(2+)-release from the sarcoplasmic or endoplasmic reticulum, the intracellular Ca(2+) store, is mediated by the ryanodine receptor (RyR) and/or the inositol trisphosphate receptor (IP3R). While IP3R is a ligand(IP3)-operated channel, RyR can be gated by a ligand (Ca(2+)) and/or mechanical coupling with the voltage sensor. There are three genetically distinct isoforms among RyR in mammals: RyR1-3. RyR1, the primary isoform in the skeletal muscle, can be gated by direct or indirect coupling with the conformation change of the alpha 1S subunit of dihydropyridine receptor (DHPR) on the T-tubules (transversely invaginated sarcolemma) upon depolarization of skeletal muscles or by the increased cytoplasmic Ca(2+) (Ca(2+)-induced Ca(2+) release, CICR). RyR2, the primary isoform in the cardiac ventricular muscle (and, in a lesser amount, the brain), can be gated by Ca(2+) which flows in through DHPR, especially the alpha1C subunit on depolarization. RyR3 is distributed ubiquitously in various tissues and may be coexpressed with RyR1 and RyR2. RyR3 is considered to be similar to RyR2 in the respect that it can be activated by Ca(2+), in view of the lack of available evidence to show the activation by the alpha1S subunit. Therefore, it is anticipated that RyR3 might take part through CICR in Ca(2+) signaling in smooth muscle and other non-muscle cells. To address the possible involvement of the CICR mechanism in the Ca(2+) signal transduction, it is critical to assess the effect of Mg(2+) on the CICR activity and the cytoplasmic concentration of Mg(2+). In this brief review, our discussion focuses on the effects of Ca(2+) and Mg(2+) on the activity of RyR3.