Ryanodine receptor
Encyclopedia
Ryanodine receptors form a class of intracellular calcium channel
s in various forms of excitable animal tissue
like muscle
s and neuron
s. It is the major cellular mediator of calcium-induced calcium release
(CICR) in animal cell
s.
alkaloid
ryanodine
, to which they show high affinity:
s:
ions from the sarcoplasmic reticulum, an essential step in muscle contraction
. In skeletal muscle
, it is thought that activation occurs via a physical coupling to the dihydropyridine receptor, whereas, in cardiac muscle
, the primary mechanism is calcium-induced calcium release
from the sarcoplasmic reticulum .
It has been shown that calcium
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 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).
RyRs are especially important in neuron
s 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 building of the wave is done by
which forms quaternary structure of RyR along with junctin and triadin. Calsequestrin has multiple Ca2+ binding sites and binds Ca2+ ions with very low affinty so they can be easily released.
Ryanodine receptors are usually found in clusters of 3 or 4 (i.e. they are associated with each other)and it was observed that they are to some extent able to open and close simultaneously. This happens more often in physiological conditions and is less observed in vitro
.
A variety of other molecules may interact with and regulate Ryanodine receptor. For example: Dimerized Homer 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
, 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.
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.
s are associated with malignant hyperthermia
and central core disease
. RyR2 mutations play a role in stress-induced polymorphic
ventricular tachycardia
(a form of cardiac arrhythmia) and ARVD
. 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
.
The presence of antibodies
against ryanodine receptors in blood serum
has also been associated with myasthenia gravis
.
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
s in various forms of excitable animal tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
like muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
s and neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s. It is the major cellular mediator of calcium-induced calcium release
Calcium-induced calcium release
Calcium-induced calcium release is a process whereby calcium can trigger release of further calcium from the muscle sarcoplasmic reticulum. Originally proposed for skeletal muscle in the 1970s, subsequent research has revealed that it is even more pronounced in the cardiac muscle...
(CICR) in animal cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s.
Etymology
The receptors are named after the plantPlant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...
alkaloid
Alkaloid
Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...
ryanodine
Ryanodine
Ryanodine is a poisonous alkaloid found in the South American plant Ryania speciosa . It was originally used as an insecticide....
, to which they show high affinity:
Isoforms
There are multiple isoforms of ryanodine receptorReceptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
s:
- RyR1RYR1Ryanodine receptor 1 also known as skeletal muscle calcium release channel or skeletal muscle-type ryanodine receptor is a protein primarily found in skeletal muscle...
is primarily expressed in skeletal muscleSkeletal muscleSkeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle... - RyR2Ryanodine receptor 2Ryanodine receptor 2 is a protein primarily found in cardiac muscle. In humans, it is encoded by the RYR2 gene.-Interactions:Ryanodine receptor 2 has been shown to interact with PRKACA, PRKACB, PRKACG, SRI and AKAP6.-External links:* *...
in myocardium (heart muscle) - A third form, RyR3RYR3Ryanodine receptor 3 is a protein that in humans is encoded by the RYR3 gene. The protein encoded by this gene is both a calcium channel and a receptor for the plant alkaloid ryanodine. RYR3 along with RYR1 control the resting calcium ion concentration in skeletal muscle....
, is expressed more widely, but especially in the brainBrainThe brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. - There is also a fourth form found only in fish.
Physiology
Ryanodine receptors mediate the release of calciumCalcium in biology
Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
ions from the sarcoplasmic reticulum, an essential step in muscle contraction
Muscle contraction
Muscle fiber generates tension through the action of actin and myosin cross-bridge cycling. While under tension, the muscle may lengthen, shorten, or remain the same...
. In skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
, it is thought that activation occurs via a physical coupling to the dihydropyridine receptor, whereas, in cardiac muscle
Cardiac muscle
Cardiac muscle is a type of involuntary striated muscle found in the walls and histologic foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle...
, the primary mechanism is calcium-induced calcium release
Calcium-induced calcium release
Calcium-induced calcium release is a process whereby calcium can trigger release of further calcium from the muscle sarcoplasmic reticulum. Originally proposed for skeletal muscle in the 1970s, subsequent research has revealed that it is even more pronounced in the cardiac muscle...
from the sarcoplasmic reticulum .
It has been shown that calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
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 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
Positive feedback
Positive feedback is a process in which the effects of a small disturbance on a system include an increase in the magnitude of the perturbation. That is, A produces more of B which in turn produces more of A. In contrast, a system that responds to a perturbation in a way that reduces its effect is...
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).
RyRs are especially important in neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s and muscle cells. In heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
and pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
cells, another second messenger (cyclic ADP-ribose
Cyclic ADP-ribose
Cyclic ADP Ribose, frequently abbreviated as cADPR, is a cyclic adenine nucleotide with two phosphate groups present on 5' OH of the adenosine , further connected to another ribose at the 5' position, which, in turn, closes the cycle by glycosidic bonding to the nitrogen 1 of the same adenine...
) 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 CPhospholipase CPhosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
by GPCR or TRK, which leads to the production of inositol trisphosphate, which in turn activates the InsP3 receptor.
Associated proteins
Many other proteins with various functions are associated with RyR. For instance in RyR2 from luminal side it is calsequestrinCalsequestrin
Calsequestrin is a calcium-binding protein of the sarcoplasmic reticulum. The protein helps hold calcium in the cisterna of the sarcoplasmic reticulum after a muscle contraction, even though the concentration of calcium in the sarcoplasmic reticulum is much higher than in the cytosol. It also...
which forms quaternary structure of RyR along with junctin and triadin. Calsequestrin has multiple Ca2+ binding sites and binds Ca2+ ions with very low affinty so they can be easily released.
Ryanodine receptors are usually found in clusters of 3 or 4 (i.e. they are associated with each other)and it was observed that they are to some extent able to open and close simultaneously. This happens more often in physiological conditions and is less observed in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
.
Pharmacology
- Antagonists:
- RyanodineRyanodineRyanodine is a poisonous alkaloid found in the South American plant Ryania speciosa . It was originally used as an insecticide....
locks the RyRs at half-open state at nanomolar concentrations, yet fully closes them at micromolar concentration. - DantroleneDantroleneDantrolene sodium is a muscle relaxant that acts by abolishing excitation-contraction coupling in muscle cells, probably by action on the ryanodine receptor. It is the only specific and effective treatment for malignant hyperthermia, a rare, life-threatening disorder triggered by general anesthesia...
the clinically-used antagonist - Ruthenium redRuthenium redThe inorganic dye ammoniated ruthenium oxychloride, also known as Ruthenium Red, is used in histology to stain aldehyde fixed mucopolysaccharides....
- procaineProcaineProcaine is a local anesthetic drug of the amino ester group. It is used primarily to reduce the pain of intramuscular injection of penicillin, and it was also used in dentistry. Owing to the ubiquity of the trade name Novocain, in some regions procaine is referred to generically as novocaine...
, tetracaineTetracaineTetracaine is a potent local anesthetic of the ester group...
, etc. (local anesthetics)
- Ryanodine
- Activators:
- Agonist: 4-chloro-m-cresol and suraminSuraminSuramin is a drug developed by Oskar Dressel and Richard Kothe of Bayer, Germany in 1916, and is still sold by Bayer under the brand name Germanin.According to the National Cancer Institute there are no active clinical trials...
are direct agonists, i.e., direct activators. - Xanthines like caffeineCaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
and pentifyllinePentifyllinePentifylline is a vasodilator....
activate it by potentiating sensitivity to native ligand Ca.- Physiological agonist: Cyclic ADP-riboseCyclic ADP-riboseCyclic ADP Ribose, frequently abbreviated as cADPR, is a cyclic adenine nucleotide with two phosphate groups present on 5' OH of the adenosine , further connected to another ribose at the 5' position, which, in turn, closes the cycle by glycosidic bonding to the nitrogen 1 of the same adenine...
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).
- Physiological agonist: Cyclic ADP-ribose
- Agonist: 4-chloro-m-cresol and suramin
A variety of other molecules may interact with and regulate Ryanodine receptor. For example: Dimerized Homer 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
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 MicroMolarMole (unit)
The mole is a unit of measurement used in chemistry to express amounts of a chemical substance, defined as an amount of a substance that contains as many elementary entities as there are atoms in 12 grams of pure carbon-12 , the isotope of carbon with atomic weight 12. This corresponds to a value...
, 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 caffeineCaffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
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 mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s are associated with malignant hyperthermia
Malignant hyperthermia
Malignant hyperthermia or malignant hyperpyrexia is a rare life-threatening condition that is usually triggered by exposure to certain drugs used for general anesthesia; specifically, the volatile anesthetic agents and the neuromuscular blocking agent, succinylcholine...
and central core disease
Central core disease
Central core disease , also known as central core myopathy, is an autosomal dominant congenital myopathy . It was first described by Shy and Magee in 1956...
. RyR2 mutations play a role in stress-induced polymorphic
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
ventricular tachycardia
Ventricular tachycardia
Ventricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...
(a form of cardiac arrhythmia) and ARVD
Arrhythmogenic right ventricular dysplasia
Arrhythmogenic right ventricular dysplasia , also called arrhythmogenic right ventricular cardiomyopathy or arrhythmogenic right ventricular dysplasia/cardiomyopathy , is an inherited heart disease....
. 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
Neurodegeneration
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. Many neurodegenerative diseases including Parkinson’s, Alzheimer’s, and Huntington’s occur as a result of neurodegenerative processes. As research progresses, many...
diseases, like Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
The presence of antibodies
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
against ryanodine receptors in blood serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
has also been associated with myasthenia gravis
Myasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
.