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Ryanodine receptors (RyR for short) form a class of intracellular
calcium channel A calcium channel is an ion channel which shows selective permeability to calcium ions. It is sometimes synonymous with voltage-gated calcium channel, although there are also ligand-gated calcium channels. Comparison tables The following tables e ...
s in various forms of excitable animal tissue like
muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of mus ...
s and
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
s. There are three major isoforms of the ryanodine receptor, which are found in different tissues and participate in different signaling pathways involving calcium release from intracellular organelles. The RYR2 ryanodine receptor isoform is the major cellular mediator of calcium-induced calcium release (CICR) in animal cells.


Etymology

The ryanodine receptors are named after the plant
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of simila ...
ryanodine which shows a high affinity to them.


Isoforms

There are multiple isoforms of ryanodine
receptor Receptor may refer to: *Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
s: *
RyR1 Ryanodine receptor 1 (RYR-1) also known as skeletal muscle calcium release channel or skeletal muscle-type ryanodine receptor is one of a class of ryanodine receptors and a protein found primarily in skeletal muscle. In humans, it is encoded by ...
is primarily expressed in
skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of m ...
*
RyR2 Ryanodine receptor 2 (RYR2) is one of a class of ryanodine receptors and a protein found primarily in cardiac muscle. In humans, it is encoded by the ''RYR2'' gene. In the process of cardiac calcium-induced calcium release, RYR2 is the major med ...
is primarily expressed in
myocardium Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle tha ...
(heart muscle) * RyR3 is expressed more widely, but especially in the
brain A brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as Visual perception, vision. I ...
. * 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 IP3 Receptors.


Physiology

Ryanodine receptors mediate the release of
calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
ions from the sarcoplasmic reticulum and
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
, an essential step in
muscle contraction Muscle contraction is the activation of tension-generating sites within muscle cells. In physiology, muscle contraction does not necessarily mean muscle shortening because muscle tension can be produced without changes in muscle length, such a ...
. In
skeletal muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of m ...
, activation of ryanodine receptors occurs via a physical coupling to the dihydropyridine receptor (a voltage-dependent, L-type calcium channel), whereas, in
cardiac muscle Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated 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 Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
release from a number of ryanodine receptors in a ryanodine receptor cluster results in a spatiotemporally restricted rise in cytosolic calcium that can be visualised as a '' calcium spark''. Ryanodine receptors are very close to mitochondria and 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) 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 therefore 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
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
s and
muscle cell A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a mus ...
s. In
heart The heart is a muscular Organ (biology), organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as ca ...
and
pancreas The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an ...
cells, another second messenger (
cyclic ADP-ribose Cyclic ADP Ribose, frequently abbreviated as cADPR, is a cyclic adenine nucleotide (like cAMP) with two phosphate groups present on 5' OH of the adenosine (like ADP), further connected to another ribose at the 5' position, which, in turn, closes ...
) takes part in the receptor activation. The localized and time-limited activity of Ca2+ in the cytosol is also called a ''Ca2+ wave''. The building of the wave is done by * the feedback mechanism of the ryanodine receptor * the activation of
phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
by GPCR or RTK, which leads to the production of inositol trisphosphate, which in turn activates the InsP3 receptor.


Associated proteins

RyRs form docking platforms for a multitude of proteins and small molecule ligands. The cardiac-specific isoform of the receptor (RyR2) is known to form a quaternary complex with luminal calsequestrin,
junctin Aspartyl/asparaginyl beta-hydroxylase (''HAAH'') is an enzyme that in humans is encoded by the ''ASPH'' gene. ASPH is an alpha-ketoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins. Function This gene is thought ...
, and
triadin Triadin, also known as TRDN, is a human gene associated with the release of calcium ions from the sarcoplasmic reticulum triggering muscular contraction through calcium-induced calcium release. Triadin is a multiprotein family, arising from differ ...
. Calsequestrin has multiple Ca2+ binding sites and binds Ca2+ ions with very low affinity so they can be easily released.


Pharmacology

*Antagonists: ** Ryanodine locks the RyRs at half-open state at nanomolar concentrations, yet fully closes them at micromolar concentration. ** Dantrolene the clinically used antagonist **
Ruthenium red The inorganic dye ammoniated ruthenium oxychloride, also known as ruthenium red, is used in histology to stain aldehyde fixed mucopolysaccharides. Ruthenium red (RR) has also been used as a pharmacological tool to study specific cellular mechanis ...
** procaine, tetracaine, etc. (local anesthetics) *Activators: **Agonist: 4-chloro-m-cresol and suramin are direct agonists, i.e., direct activators. **Xanthines like
caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class. It is mainly recreational drug use, used recreationally as a Nootropic, cognitive enhancer, increasing alertness and attentional perfor ...
and pentifylline activate it by potentiating sensitivity to native ligand Ca. **Physiological agonist:
Cyclic ADP-ribose Cyclic ADP Ribose, frequently abbreviated as cADPR, is a cyclic adenine nucleotide (like cAMP) with two phosphate groups present on 5' OH of the adenosine (like ADP), further connected to another ribose at the 5' position, which, in turn, closes ...
can act as a physiological gating agent. It has been suggested that it may act by making FKBP12.6 (12.6 kilodalton FK506 binding protein, as opposed to 12 kDa FKBP12 which binds to RyR1) which normally bind (and blocks) RyR2 channel tetramer in an average stoichiometry of 3.6, to fall off RyR2 (which is the predominant RyR in pancreatic beta cells, cardiomyocytes and smooth muscles). A variety of other molecules may interact with and regulate ryanodine receptor. For example: dimerized
Homer Homer (; grc, Ὅμηρος , ''Hómēros'') (born ) was a Greek poet who is credited as the author of the ''Iliad'' and the ''Odyssey'', two epic poems that are foundational works of ancient Greek literature. Homer is considered one of the ...
physical tether linking inositol trisphosphate receptors (IP3R) and ryanodine receptors on the intracellular calcium stores with cell surface group 1 metabotropic glutamate receptors and the
Alpha-1D adrenergic receptor The alpha-1D adrenergic receptor (α1D adrenoreceptor), also known as ADRA1D, is an alpha-1 adrenergic receptor, and also denotes the human gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe th ...


Ryanodine

The plant alkaloid ryanodine, for which this receptor was named, has become an invaluable investigative tool. It can block the phasic release of calcium, but at low doses may not block the tonic cumulative calcium release. The binding of ryanodine to RyRs is ''use-dependent'', that is the channels have to be in the activated state. At low (<10 micro molar, works even at nanomolar) concentrations, ryanodine binding locks the RyRs into a long-lived subconductance (half-open) state and eventually depletes the store, while higher (~100 micromolar) concentrations irreversibly inhibit channel-opening.


Caffeine

RyRs are activated by millimolar
caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class. It is mainly recreational drug use, used recreationally as a Nootropic, cognitive enhancer, increasing alertness and attentional perfor ...
concentrations. High (greater than 5 mmol/L) caffeine concentrations cause a pronounced increase (from micromolar to picomolar) in the sensitivity of RyRs to Ca2+ in the presence of caffeine, such that basal Ca2+ concentrations become activatory. At low millimolar caffeine concentrations, the receptor opens in a quantal way, but has complicated behavior in terms of repeated use of caffeine or dependence on cytosolic or luminal calcium concentrations.


Role in disease

RyR1
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s are associated with
malignant hyperthermia Malignant hyperthermia (MH) is a type of severe reaction that occurs in response to particular medications used during general anesthesia, among those who are susceptible. Symptoms include muscle rigidity, fever, and a fast heart rate. Complica ...
and central core disease. RyR2 mutations play a role in stress-induced polymorphic
ventricular tachycardia Ventricular tachycardia (V-tach or VT) is a fast heart rate arising from the lower chambers of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short period ...
(a form of
cardiac arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adult ...
) and
ARVD Arrhythmogenic cardiomyopathy (ACM), arrhythmogenic right ventricular dysplasia (ARVD), or arrhythmogenic right ventricular cardiomyopathy (ARVC), most commonly is an inherited heart disease. ACM is caused by genetic defects of the parts of hear ...
. It has also been shown that levels of type RyR3 are greatly increased in PC12 cells overexpressing mutant human Presenilin 1, and in brain tissue in knockin mice that express mutant Presenilin 1 at normal levels, and thus may play a role in the pathogenesis of neurodegenerative diseases, like
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...
. The presence of
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of ...
against ryanodine receptors in blood serum has also been associated with myasthenia gravis. Sudden cardiac death in several young individuals in the Amish community (four of which were from the same family) was traced to homozygous duplication of a mutant RyR2 (Ryanodine Receptor) gene. Normal (wild type) ryanodine receptors are involved in CICR in heart and other muscles, and RyR2 functions primarily in the myocardium (heart muscle).


Structure

RyR1 cryo-EM structure revealed a large cytosolic assembly built on an extended α-solenoid scaffold connecting key regulatory domains to the pore. The RyR1 pore architecture shares the general structure of the six-transmembrane ion channel superfamily. A unique domain inserted between the second and third transmembrane helices interacts intimately with paired EF-hands originating from the α-solenoid scaffold, suggesting a mechanism for channel gating by Ca2+.


See also

*
Ryanoid Ryanoids are a class of insecticides which share the same mechanism of action as the alkaloid ryanodine. Ryanodine is a naturally occurring insecticide isolated from '' Ryania speciosa''. Ryanoids include natural chemicals which are closely relate ...
, a class of insecticide that act through ryanodine receptors


References


External links

* {{Calcium signaling Transmembrane receptors Calcium channels