Ryanodine receptors (RyR) are classified as high-conductance, intracellular calcium release channels, typically present in the membrane of the sarcoplasmic and endoplasmic reticulum. The major role these channels play is to regulate cell signaling and muscle contraction by releasing calcium ions. There are three major isoforms of the ryanodine receptor (RyR1, RyR2, and RyR3), which are found in different tissues and participate in various signaling pathways involving calcium release from intracellular organelles. RyR1 is responsible for skeletal muscle contraction, RyR2 is responsible for cardiac muscle contraction, and RyR3 is responsible for maintaining calcium homeostasis in the brain and throughout other tissues in the body.
Origin The ryanodine receptors were originally identified in the 1980s and named after the plant alkaloid ryanodine, found in Central and South America. When ryanodine was first found it was investigated to be a potential insecticide due to its ability to induce paralysis amongst insects. Later research saw that ryanodine had a high binding affinity to the sarcoplasmic reticulum in muscle cells, which allowed researchers to turn ryanodine into a high affinity ligand responsible for finding its purified receptor. The purified receptor turned out to be a calcium release channel, responsible for controlling the movement of calcium from stores in the cardiac and skeletal tissue.
Structure Ryanodine receptors are known as one of the largest ion channels that form multidomain homotetramers. These domains regulate intracellular calcium ions to release from the sarcoplasmic and endoplasmic reticula. These receptors have weights exceeding 2 megadaltons and their structural complexity enables a wide variety of allosteric regulation mechanisms. Due to these receptors size and structure they are able to integrate regulatory signals and readily control the rate of calcium release. Studies involving cryo-electron microscopy (cryo-EM) have revealed 3-D structures of Ryanodine receptors. It has been shown that RyR's have fourfold symmetry and adopt a mushroom-like structure: a large cytosolic assembly that forms the "cap" and smaller transmembrane regions that form the "stalk", which is embedded into the sarco/endoplasmatic reticulum's membrane. The bulk of the receptors, approximately 80% of the mass, are present in the cytosolic domain, which accounts for the many regulatory interactions. The cytosolic portion of the structure is made up of an extended α-solenoid scaffold which is able to connect regulatory domains to the ion conducting pores found in the transmembrane region. This allows the receptor to gather and read diverse signal inputs. Also, due to the transmembrane region containing ion conducting pores that puts RyR's in the six-transmembrane ion channel superfamily. Additionally, there is a unique domain inserted between the second and third transmembrane helices which interacts intimately with paired EF-hands originating from the α-solenoid scaffold, suggesting a mechanism for channel gating by Ca2+. Each major ryanodine receptor isoform (RyR1, RyR2, and RyR3) share a similar structure with minor differences that depend on where they are located and how they function, i.e. heart or skeletal muscle.
Isoforms There are multiple isoforms of ryanodine receptors:
RyR1 is primarily expressed in skeletal muscle It is essential for excitation-contraction coupling RyR2 is primarily expressed in myocardium (heart muscle) the major cellular mediator of calcium-induced calcium release (CICR) in animal cells. RyR3 is expressed more widely, but especially in the brain. It is involved in neuroprotection, memory, pain modulation, and social behavior. Non-mammalian vertebrates typically express two RyR isoforms, referred to as RyR-alpha and RyR-beta. Many invertebrates, including the model organisms Drosophila melanogaster (fruitfly) and Caenorhabditis elegans, only have a single isoform. In non-metazoan species, calcium-release channels with sequence homology to RyRs can be found, but they are shorter than the mammalian ones and may be closer to inositol trisphosphate (IP3) receptors.
Physiology
Ryanodine receptors mediate the release of calcium ions from the sarcoplasmic reticulum and endoplasmic reticulum, an essential step in muscle contraction. In skeletal muscle, activation of ryanodine receptors occurs via a physical coupling to the dihydropyridine receptor (a voltage-dependent, L-type calcium channel), whereas in cardiac muscle, the primary mechanism of activation is calcium-induced calcium release, which causes calcium outflow from the sarcoplasmic reticulum. It has been shown that calcium release from a number of ryanodine receptors in a RyR cluster results in a spatiotemporally-restricted rise in cytosolic calcium that can be visualized as a calcium spark. Calcium release from RyR has been shown to regulate ATP production in heart and pancreas cells. Ryanodine receptors are similar to the inositol trisphosphate (IP3 or InsP3) receptor, and stimulated to transport Ca2+ into the cytosol by recognizing Ca2+ on its cytosolic side, thus establishing a positive feedback mechanism; a small amount of Ca2+ in the cytosol near the receptor will cause it to release even more Ca2+ (calcium-induced calcium release/CICR). However, as the concentration of intracellular Ca2+ rises, this can trigger closing of RyR, preventing the total depletion of SR. This finding indicates that a plot of opening probability for RyR as a function of Ca2+ concentration is a bell-curve. Furthermore, RyR can sense the Ca2+ concentration inside the ER/SR and spontaneously open in a process known as store overload-induced calcium release (SOICR). RyRs are especially important in neurons and muscle cells. In heart and pancreas cells, another second messenger (cyclic ADP-ribose) takes part in the receptor activation. The localized and time-limited activity of Ca2+ in the cytosol is also called a Ca2+ wave. The propagation of the wave is accomplished by the feedback mechanism of the ryanodine receptor. The activation of phospholipase C by GPCR or RTK triggers the production of inositol trisphosphate, which activates of the InsP3 receptor.
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