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 channels 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 generating a Ca2+ conducting channel . They play a key role in the mechanism of excitation-contraction coupling in striated muscle. Binding of Ryanodine to the Ryanodine Receptor causes to two major changes in the channel: a reduction in single-channel conductance and a marked increase in open state probability.
The RyR1 is expressed predominantly in skeletal muscles and areas of the brain; the human RyR1 has at least three known alternative spliced variants.5
Several diseases are attributed to mutations in RyR1 gene: Central Core Disease (CCD), multi-minicore disease (MmD) and Malignant Hyperthermia (MH).5
