Ryanodine receptor 2 (RYR2) is one of a class of

ryanodine receptor Ryanodine receptors (RyR) make up a class of high-conductance, intracellular calcium channels present in various forms, such as animal muscles and neurons. There are three major isoforms of the ryanodine receptor, which are found in different tissu ...

s and a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

found primarily in

cardiac muscle Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall o ...

. In humans, it is encoded by the ''RYR2''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. In the process of cardiac calcium-induced calcium release, RYR2 is the major mediator for sarcoplasmic release of stored calcium ions.

Structure

The channel is composed of RYR2 homotetramers and FK506-binding proteins found in a 1:4 stoichiometric ratio. Calcium channel function is affected by the specific type of FK506 isomer interacting with the RYR2 protein, due to binding differences and other factors.

Function

The RYR2 protein functions as the major component of a calcium channel located in the sarcoplasmic reticulum that supplies ions to the

during

systole Systole ( ) is the part of the cardiac cycle during which some chambers of the heart contract after refilling with blood. Its contrasting phase is diastole, the relaxed phase of the cardiac cycle when the chambers of the heart are refilling ...

. To enable cardiac muscle contraction, calcium influx through voltage-gated L-type calcium channels in the plasma membrane allows calcium ions to bind to RYR2 located on the sarcoplasmic reticulum. This binding causes the release of calcium through RYR2 from the sarcoplasmic reticulum into the cytosol, where it binds to the C domain of

troponin Troponin, or the troponin complex, is a complex of three regulatory proteins (troponin C, troponin I, and troponin T) that are integral to muscle contraction in skeletal muscle and cardiac muscle, but not smooth muscle. Measurements of cardiac-spe ...

, which shifts

tropomyosin Tropomyosin is a two-stranded alpha-helical, coiled coil protein found in many animal and fungal cells. In animals, it is an important component of the muscular system which works in conjunction with troponin to regulate muscle contraction. It ...

and allows the

myosin Myosins () are a Protein family, family of motor proteins (though most often protein complexes) best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are adenosine triphosphate, ATP- ...

ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, ATP hydrolase, adenosine triphosphatase) are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion or ...

to bind to

actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ...

, enabling cardiac muscle contraction. RYR2 channels are associated with many cellular functions, including mitochondrial metabolism, gene expression and cell survival, in addition to their role in cardiomyocyte contraction.

Clinical significance

Deleterious mutations of the ryanodine receptor family, and especially the RYR2 receptor, lead to a constellation of pathologies leading to both acute and chronic heart failure collectively known as "Ryanopathies." Mutations in the ''RYR2'' gene are associated with catecholaminergic polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. Recently, 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 gene. Normal (wild type) RyR2 functions primarily in the myocardium (heart muscle). Mice with genetically reduced RYR2 exhibit a lower basal heart rate and fatal arrhythmias.

Interactions

Ryanodine receptor 2 has been shown to interact with: *

Protein kinase A In cell biology, protein kinase A (PKA) is a family of serine-threonine kinases whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, in ...

( AKAP6,

PRKACA The catalytic subunit α of protein kinase A is a key regulatory enzyme that in humans is encoded by the ''PRKACA'' gene. This enzyme is responsible for phosphorylating other proteins and substrates, changing their activity. Protein kinase A catal ...

PRKACB cAMP-dependent protein kinase catalytic subunit beta is an enzyme that in humans is encoded by the ''PRKACB'' gene. cAMP is a signaling molecule important for a variety of cellular functions. cAMP exerts its effects by activating the protein ki ...

PRKACG cAMP-dependent protein kinase catalytic subunit gamma is an enzyme that in humans is encoded by the ''PRKACG'' gene. Cyclic AMP-dependent protein kinase (PKA) consists of two catalytic subunits and a regulatory subunit dimer. This gene encodes ...

,) (phosphorylation at serine position S2808 in rodents) *

CaMKII /calmodulin-dependent protein kinase II (CaM kinase II or CaMKII) is a serine/threonine-specific protein kinase that is regulated by the /calmodulin complex. CaMKII is involved in many signaling cascades and is thought to be an important mediat ...

(via phosphorylation at serine positions S2808 and S2814 in humans and rodents, S2809 and S2815 in rabbits) * SRI *

Protein phosphatase 1 Protein phosphatase 1 (PP1) belongs to a certain class of phosphatases known as protein serine/threonine phosphatases. This type of phosphatase includes metal-dependent protein phosphatases (PPMs) and aspartate-based phosphatases. PP1 has been fo ...

(dephosphorylation at serine positions S2808 and S2814 in rodents) *

Protein phosphatase 2 Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the ''PPP2CA'' gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in ...

(dephosphorylation at serine position S2814 in rodents)

References

External links

GeneReviews/NCBI/NIH/UW entry on Catecholaminergic Polymorphic Ventricular Tachycardia

GeneReviews/NCBI/NIH/UW entry on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant

OMIM entries on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant
* {{Ion channels, g1 Ion channels EF-hand-containing proteins