It is well established that cytosolic calcium (Ca²⁺) acts as a key second messenger in many intracellular pathways including synaptic transmission, muscle contraction, hormonal secretion, cell growth and proliferation.^1,2  The primary intracellular Ca²⁺ storage/release organelle in most cells is the endoplasmic reticulum (ER) or the sarcoplasmic reticulum (SR) in striated muscle cells.

The ER and SR contain two Ca²⁺ release channel families, the inositol trisphosphate receptors (IP₃Rs) and the ryanodine receptors (RyRs).³

The ryanodine receptor family consists of three different isoforms: the skeletal muscle isoform, ryanodine receptor type 1 (RyR1); the cardiac muscle isoform, ryanodine receptor type 2 (RyR2) and the brain isoform, ryanodine receptor type 3 (RyR3).³

The ryanodine receptors are homotetrameric proteins, which upon assembly create a Ca²⁺ conducting channel. They play a key role in the mechanism of excitation-contraction coupling in striated muscle. Binding of ryanodine (a poisonous alkaloid found in the South American plant Ryania speciosa) to the ryanodine receptor causes two major changes in the channel: a reduction in single-channel conductance and a marked increase in the open state probability, leading to an overall increase/decrease in the Ca²⁺ release capability of the channel.

RyR3 is the most widely expressed RyR channel which is predominantly expressed in smooth muscle tissues and certain regions of the brain.