Gene Report

Basic Information

Approved Symbol	RYR2
Approved Name	ryanodine receptor 2 (cardiac)
Previous Symbol	ARVD2
Previous Name	"arrhythmogenic right ventricular dysplasia 2"
Symbol Alias	ARVC2, VTSIP
Location	1q43
Position	chr1:237995948-237997288 (+)
External Links	Entrez Gene: 6262 Ensembl: ENSG00000198626 UCSC: uc001hyl.1 HGNC ID: 10484
No. of Studies (Positive/Negative)	1(1/0)
Type	Literature-origin

Positive relationships between RYR2 and MDD (count: 1)

Name in Literature	Reference	Research Type	Statistical Result	Relation Description
RYR2	Guilloux JP, 2012	patients and normal controls		genes significantly affected in female MDD subjects genes significantly affected in female MDD subjects

Positive relationships between RYR2 and other components at different levels (count: 0)

Positive relationship network of RYR2 in MK4MDD

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Note:
1. The different color of the nodes denotes the level of the nodes.

Genetic/Epigenetic Locus	Protein and Other Molecule	Cell and Molecular Pathway	Neural System	Cognition and Behavior	Symptoms and Signs	Environment	MDD

2. Besides the component related relationships from literature, gene mapped protein and protein mapped gene are also shown in the network. If the mapped gene or protein is not from literature, square node would be used instead of Circle node. Accordingly, the relationship is marked with dot line.
2. User can drag the nodes to rearrange the layout of the network. Click the node will enter the report page of the node. Right-click will show also the menus to link to the report page of the node and remove the node and related edges. Hover the node will show the level of the node and hover the edge will show the evidence/description of the edge.
3. The network is generated using Cytoscape Web

Negative relationships between RYR2 and MDD (count: 0)

Negative relationships between RYR2 and other components at different levels (count: 0)

RYR2 related SNPs in MK4MDD (count: 0)

RYR2 related proteins in MK4MDD (count: 0)

RYR2 related GO terms (count: 69)

ID	Name	Type	Evidence
Gene mapped GO terms
GO:0034704	calcium channel complex	cellular component	IDA[10830164\|16213210]
GO:0005509	calcium ion binding	molecular function	IEA
GO:0010881	regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	biological process	IC[19220289]; ISS
GO:0048763	calcium-induced calcium release activity	molecular function	IDA[17921453]
GO:0071313	cellular response to caffeine	biological process	IDA[12919952]; ISS
GO:0019722	calcium-mediated signaling	biological process	ISS
GO:0030018	Z disc	cellular component	ISS
GO:0070296	sarcoplasmic reticulum calcium ion transport	biological process	TAS[19095005]
GO:0098735	positive regulation of the force of heart contraction	biological process	IMP[15105296]
GO:0035584	calcium-mediated signaling using intracellular calcium source	biological process	IDA[17921453]
GO:0005790	smooth endoplasmic reticulum	cellular component	IEA
GO:0033017	sarcoplasmic reticulum membrane	cellular component	ISS; TAS[19095005]
GO:0055085	transmembrane transport	biological process	TAS
GO:0042802	identical protein binding	molecular function	IPI[10830164]
GO:0003300	cardiac muscle hypertrophy	biological process	ISS
GO:0043234	protein complex	cellular component	IDA[18468998]
GO:0043621	protein self-association	molecular function	IEA
GO:0015278	calcium-release channel activity	molecular function	IDA[17921453]
GO:0006874	cellular calcium ion homeostasis	biological process	ISS
GO:0001666	response to hypoxia	biological process	ISS
GO:0031000	response to caffeine	biological process	IDA[17921453]
GO:0005515	protein binding	molecular function	IPI[10830164\|11237759\|17921453\|20195357\|23233753]
GO:0014701	junctional sarcoplasmic reticulum membrane	cellular component	TAS[17569730]
GO:0060402	calcium ion transport into cytosol	biological process	IDA[17921453]
GO:0051284	positive regulation of sequestering of calcium ion	biological process	IDA[12443530\|12919952]
GO:0030509	BMP signaling pathway	biological process	IEA
GO:0051775	response to redox state	biological process	IDA[19226252]
GO:0086064	cell communication by electrical coupling involved in cardiac conduction	biological process	IC
GO:0034237	protein kinase A regulatory subunit binding	molecular function	IDA[10830164]
GO:0060048	cardiac muscle contraction	biological process	IMP[10830164]
GO:0044325	ion channel binding	molecular function	ISS
GO:0014850	response to muscle activity	biological process	IMP[17875969]
GO:0002027	regulation of heart rate	biological process	IMP[11159936\|12919952\|15197150]
GO:0098907	regulation of SA node cell action potential	biological process	IMP[17875969]
GO:0016529	sarcoplasmic reticulum	cellular component	IDA[10830164\|12919952]
GO:0005886	plasma membrane	cellular component	ISS
GO:0003220	left ventricular cardiac muscle tissue morphogenesis	biological process	ISS
GO:1903779	regulation of cardiac conduction	biological process	TAS
GO:0055117	regulation of cardiac muscle contraction	biological process	IMP[11159936]
GO:0003143	embryonic heart tube morphogenesis	biological process	ISS
GO:0061337	cardiac conduction	biological process	TAS
GO:0086029	Purkinje myocyte to ventricular cardiac muscle cell signaling	biological process	ISS
GO:0034220	ion transmembrane transport	biological process	TAS
GO:0071872	cellular response to epinephrine stimulus	biological process	ISS; TAS[23507255]
GO:0006816	calcium ion transport	biological process	IDA[17921453]
GO:0014808	release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	biological process	IMP[12919952]; ISS
GO:1901896	positive regulation of calcium-transporting ATPase activity	biological process	IDA[12443530]
GO:0010882	regulation of cardiac muscle contraction by calcium ion signaling	biological process	IMP[17875969]
GO:0072599	establishment of protein localization to endoplasmic reticulum	biological process	IDA[12443530]
GO:0086005	ventricular cardiac muscle cell action potential	biological process	ISS
GO:0005516	calmodulin binding	molecular function	IMP[19220289]; IPI[23040497]; ISS
GO:0043924	suramin binding	molecular function	IMP[19220289]
GO:0051209	release of sequestered calcium ion into cytosol	biological process	IDA[12443530\|17921453]; ISS
GO:0005262	calcium channel activity	molecular function	ISS
GO:0034236	protein kinase A catalytic subunit binding	molecular function	IDA[10830164]
GO:0070062	extracellular exosome	cellular component	IDA[23376485]
GO:0010460	positive regulation of heart rate	biological process	ISS
GO:0098910	regulation of atrial cardiac muscle cell action potential	biological process	IMP[17875969]
GO:0097050	type B pancreatic cell apoptotic process	biological process	IMP[15044459]
GO:0005219	ryanodine-sensitive calcium-release channel activity	molecular function	IDA[17921453]
GO:0098911	regulation of ventricular cardiac muscle cell action potential	biological process	IMP[17875969]
GO:0019899	enzyme binding	molecular function	IPI[16213210]
GO:0051480	regulation of cytosolic calcium ion concentration	biological process	ISS
GO:0016020	membrane	cellular component	IDA[12443530]
GO:0005829	cytosol	cellular component	ISS
GO:0060070	canonical Wnt signaling pathway	biological process	IEA
GO:0035994	response to muscle stretch	biological process	IMP[15105296]
GO:0098904	regulation of AV node cell action potential	biological process	IMP[17875969]
GO:0005513	detection of calcium ion	biological process	IDA[10830164]

RYR2 related KEGG pathways (count: 5)

ID	Name	Brief Description	Full Description
Literature-origin KEGG pathway
hsa04020	calcium signaling_pathway	Calcium signaling pathway	Ca2+ that enters the cell from the outside is a principal so...... Ca2+ that enters the cell from the outside is a principal source of signal Ca2+. Entry of Ca2+ is driven by the presence of a large electrochemical gradient across the plasma membrane. Cells use this external source of signal Ca2+ by activating various entry channels with widely different properties. The voltage-operated channels (VOCs) are found in excitable cells and generate the rapid Ca2+ fluxes that control fast cellular processes. There are many other Ca2+-entry channels, such as the receptor-operated channels (ROCs), for example the NMDA (N-methyl-D-aspartate) receptors (NMDARs) that respond to glutamate. There also are second-messenger-operated channels (SMOCs) and store-operated channels (SOCs). The other principal source of Ca2+ for signalling is the internal stores that are located primarily in the endoplasmic/sarcoplasmic reticulum (ER/SR), in which inositol-1,4,5-trisphosphate receptors (IP3Rs) or ryanodine receptors (RYRs) regulate the release of Ca2+. The principal activator of these channels is Ca2+ itself and this process of Ca2+-induced Ca2+ release is central to the mechanism of Ca2+ signalling. Various second messengers or modulators also control the release of Ca2+. IP3, which is generated by pathways using different isoforms of phospholipase C (PLCbeta, delta, epsilon, gamma and zeta), regulates the IP3Rs. Cyclic ADP-ribose (cADPR) releases Ca2+ via RYRs. Nicotinic acid adenine dinucleotide phosphate (NAADP) may activate a distinct Ca2+ release mechanism on separate acidic Ca2+ stores. Ca2+ release via the NAADP-sensitive mechanism may also feedback onto either RYRs or IP3Rs. cADPR and NAADP are generated by CD38. This enzyme might be sensitive to the cellular metabolism, as ATP and NADH inhibit it. The influx of Ca2+ from the environment or release from internal stores causes a very rapid and dramatic increase in cytoplasmic calcium concentration, which has been widely exploited for signal transduction. Some proteins, such as troponin C (TnC) involved in muscle contraction, directly bind to and sense Ca2+. However, in other cases Ca2+ is sensed through intermediate calcium sensors such as calmodulin (CALM). More...
hsa05412	arrhythmogenic right_ventricular_cardiomyopathy_arvc	Arrhythmogenic right ventricular cardiomyopathy (ARVC)	Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an...... Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that may result in arrhythmia, heart failure, and sudden death. The hallmark pathological findings are progressive myocyte loss and fibrofatty replacement, with a predilection for the right ventricle. A number of genetic studies have identified mutations in various components of the cardiac desmosome that have important roles in the pathogenesis of ARVD/C. Disruption of desmosomal function by defective proteins might lead to death of myocytes under mechanical stress. The myocardial injury may be accompanied by inflammation. Since regeneration of cardiac myocytes is limited, repair by fibrofatty replacement occurs. Several studies have implicated that desmosome dysfunction results in the delocalization and nuclear translocation of plakoglobin. As a result, competition between plakoglobin and beta-catenin will lead to the inhibition of Wnt/beta-catenin signaling, resulting in a shift from a myocyte fate towards an adipocyte fate of cells. The ryanodine receptor plays a crucial part in electromechanical coupling by control of release of calcium from the sarcoplasmic reticulum into the cytosol. Therefore, defects in this receptor could result in an imbalance of calcium homeostasis that might trigger cell death. More...

ID	Name	Brief Description	Full Description
Gene mapped KEGG pathways
hsa04260	cardiac muscle_contraction	Cardiac muscle contraction	Contraction of the heart is a complex process initiated by t...... Contraction of the heart is a complex process initiated by the electrical excitation of cardiac myocytes (excitation-contraction coupling, ECC). In cardiac myocytes, Ca2+ influx induced by activation of voltage-dependent L-type Ca channels (DHP receptors) upon membrane depolarization triggers the release of Ca2+ via Ca2+ release channels (ryanodine receptors) of sarcoplasmic reticulum (SR) through a Ca2+ -induced Ca release (CICR) mechanism. Ca2+ ions released via the CICR mechanism diffuse through the cytosolic space to contractile proteins to bind to troponinC resulting in the release of inhibition induced by troponinI. The Ca2+ binding to troponinC thereby triggers the sliding of thin and thick filaments, that is, the activation of a crossbridge and subsequent cardiac force development and/or cell shortening. Recovery occurs as Ca2+ is pumped out of the cell by the Na+/Ca2+ exchanger (NCX) or is returned to the sarcoplasmic reticulum (SR) by sarco(endo)plasmic Ca2+ -ATPase (SERCA) pumps on the non-junctional region of the SR. More...
hsa05410	hypertrophic cardiomyopathy_hcm	Hypertrophic cardiomyopathy (HCM)	Hypertrophic cardiomyopathy (HCM) is a primary myocardial di...... Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder with an autosomal dominant pattern of inheritance that is characterized by hypertrophy of the left ventricles with histological features of myocyte hypertrophy, myofibrillar disarray, and interstitial fibrosis. HCM is one of the most common inherited cardiac disorders, with a prevalence in young adults of 1 in 500. Hundreds of mutations in 11 genes that encode protein constituents of the sarcomere have been identified in HCM. These mutations increase the Ca2+ sensitivity of cardiac myofilaments. Increased myofilament Ca2+ sensitivity is expected to increase the ATP utilization by actomyosin at submaximal Ca2+ concentrations, which might cause an imbalance in energy supply and demand in the heart under severe stress. The inefficient use of ATP suggests that an inability to maintain normal ATP levels could be the central abnormality. This theory might be supported by the discovery of the role of a mutant PRKAG2 gene in HCM, which in active form acts as a central sensing mechanism protecting cells from depletion of ATP supplies. The increase in the myofilament Ca2+ sensitivity well account for the diastolic dysfunction of model animals as well as human patients of HCM. It has been widely proposed that left ventricular hypertrophy is not a primary manifestation but develops as compensatory response to sarcomere dysfunction. More...
hsa05414	dilated cardiomyopathy	Dilated cardiomyopathy	Dilated cardiomyopathy (DCM) is a heart muscle disease chara...... Dilated cardiomyopathy (DCM) is a heart muscle disease characterised by dilation and impaired contraction of the left or both ventricles that results in progressive heart failure and sudden cardiac death from ventricular arrhythmia. Genetically inherited forms of DCM (familial DCM) have been identified in 25-35% of patients presenting with this disease, and the inherited gene defects are an important cause of familial DCM. The pathophysiology may be separated into two categories: defects in force generation and defects in force transmission. In cases where an underlying pathology cannot be identified, the patient is diagnosed with an idiopathic DCM. Current hypotheses regarding causes of idiopathic DCM focus on chronic viral myocarditis and/or on autoimmune abnormalities. Viral myocarditis may progress to an autoimmune phase and then to progressive cardiac dilatation. Antibodies to the beta1-adrenergic receptor (beta1AR), which are detected in a substantial number of patients with idiopathic DCM, may increase the concentration of intracellular cAMP and intracellular Ca2+, a condition often leading to a transient hyper-performance of the heart followed by depressed heart function and heart failure. More...

RYR2 related BioCarta pathways (count: 1)

ID	Name	Brief Description	Full Description
Gene mapped BioCarta pathways
NO1_PATHWAY	no1 pathway	Actions of Nitric Oxide in the Heart	Nitric oxide (NO) has a number of important physiological ac...... Nitric oxide (NO) has a number of important physiological actions in the cardiovascular system. In the heart, NO plays role in keeping the vessels patent via vasodilation and prevention of platelet aggregation. It also plays an important role in regulating the force and rate of contraction. In vivo NO is released by shear stress of ligands that increase intracellular Ca2+ in endothelial cells. The increase intracellular Ca2+ activates nitric oxide synthase III (NOSIII) by promoting the binding of Ca/Calmodulin to the enzyme. NOSIII, which is resident in the Golgi complex, is transported together with caveolin-1 to the caveolae at the plasma membrane via vesicles. Shear stress signals via a potassium channel and the cytoskeleton, which results in tyrosine phosphorylation of specific proteins, activation of phosphatidylinositol 3-kinase, and subsequently in activation of Akt kinase. Akt activation by shear stress but also by VEGF activates NOSIII by serine phosphorylation, which increases the affinity of NOSIII for calmodulin. After agonist binding at the plasma membrane, NOSIII-activating receptors translocate to caveolae. VEGF receptor signals via its tyrosine kinase domain. Furthermore, agonist receptors activate calcium channels of the endoplasmic reticulum (ER) via phospholipase C and inositol 1,4,5-trisphosphate. This calcium flux induces binding of calmodulin to NOSIII, whereas the NOSIII-caveolin-1 interaction is disrupted. At the same time, NOSIII is translocated into the cytosol. On binding of calmodulin, NOSIII generates NO, is enhanced by the interaction with Hsp90. Once activated, NOSIII catabolizes L-arginine to NO, which diffuses out of the cell. NO stimulates guanylate (G-) cyclase and increases cGMP levels. cGMP activates cGMP-dependent protein kinase (PKG), cGMP-inhibited phosphodiesterase (PDEIII), and cGMP-stimulated phosphodiesterase (PDEII). PKG may reduce the force and rate of contraction, possibly by phosphorylating troponin I or by phosphorylating phospholamban. PDEIII is inhibited by the increases in cGMP brought about by NO. This may result in an increase in cAMP and cAMP-dependent protein kinase (PKA). PKA in turn activates Ca2+ channels, countering the effects of PKG. In contrast, cGMP may stimulate PDEII, reduce cAMP levels and PKA activity, and thereby reduce Ca2+ channel activity. Ach, acetylcholine. CAT-1, cationic amino acid transporter. More...

RYR2 related Reactome pathways (count: 0)

RYR2 related interactors from protein-protein interaction data in HPRD (count: 12)

Gene	Interactor	Interactor in MK4MDD?	Experiment Type	PMID
RYR2	HOMER1	No	in vitro;in vivo	12887973
RYR2	RYR3	No	in vivo	12213830
RYR2	SRI	No	in vivo	7592856
RYR2	PRKAR2A	Yes	in vitro;in vivo	10830164
RYR2	SMAD5	No	yeast 2-hybrid	15231748
RYR2	CACNA1C	Yes	in vitro	11576544
RYR2	AKAP6	No	in vivo	11352932
RYR2	FKBP1B	No	in vitro;in vivo;yeast 2-hybrid	12446682 , 12443530 , 10830164 , 11237759
RYR2	RYR1	No	in vivo	12213830
RYR2	PRKACA	No	in vitro;in vivo	10830164
RYR2	ALB	No	in vivo	15174051
RYR2	ITPR1	Yes	in vivo	12754204

Gene Report

Gene mapped GO terms

Literature-origin KEGG pathway

Gene mapped KEGG pathways

Gene mapped BioCarta pathways