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{{Infobox_gene}}
{{Infobox_gene}}
'''Triadin''', also known as '''TRDN''', is a human [[gene]]<ref name="entrez">{{cite web | title = Entrez Gene: TRDN triadin| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10345| accessdate = }}</ref> 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 different processing of the TRDN gene on chromosome 6.<ref>{{cite journal |last=Thevenon |first=D. |last2=Smida-Rezgui |first2=S. |last3=Chevessier |first3=F. |last4=Groh |first4=S.|last5=Henry-Berger |first5=J. |last6=Romero |first6=N. B. |last7=Villaz |first7=M. |last8=De Waard |first8=M |last9=Marty |first9=I |year=2003 |title=Human skeletal muscle triadin: gene organization and cloning of the major isoform, Trisk 51 |journal=Biochem. Biophys. Res. Commun. |volume=303 |pages=669–675 |pmid=12659871 |issue=12 |doi=10.1016/s0006-291x(03)00406-6}}</ref> It is a transmembrane protein on the [[sarcoplasmic reticulum]] due to a well defined hydrophobic section<ref name="second">{{cite journal |last=Kobayashi |first=Y. M. |first2=L. R. |last2=Jones |year=1999 |title=Identification of triadin 1 as the predominant triadin isoform expressed in mammalian myocardium |journal=J. Biol. Chem. |volume=274 |pages=28660–28668 |pmid=10497235 |issue=40 |doi=10.1074/jbc.274.40.28660}}</ref><ref name="third">{{cite journal |last=Jones |first=L. R. |first2=L. |last2=Zhang |first3=K. |last3=Sanborn |first4=A. O. |last4=Jorgensen |first5=J. |last5=Kelley. |year=1995 |title=Purification, primary structure, and immunological characterization of the 26-kDa calsequestrin binding protein (junctin) from cardiac junctional sarcoplasmic reticulum |journal=J. Biol. Chem. |volume=270 |pages=30787–30796 |pmid=8530521 |issue=51 |doi=10.1074/jbc.270.51.30787}}</ref> and it forms a quaternary complex with the cardiac [[Ryanodine]] receptor ([[RYR2]]), calsequestrin ([[CASQ2]]) and [[junctin]] proteins.<ref name="second" /><ref name="third" /><ref name="fourth">{{cite journal |last=Zhang |first=L. |first2=J. |last2=Kelley, |first3=G. |last3=Schmeisser, |first4=Y. M. |last4=Kobayashi |first5=L. R. |last5=Jones |year=1997 |title=Complex formation between junctin, triadin, calsequestrin, and the ryanodine receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane. |journal=J. Biol. Chem. |volume=272 |pages=23389–23397 |pmid=9287354 |doi=10.1074/jbc.272.37.23389}}</ref><ref name="fifth">{{cite journal |last=Kobayashi |first=Y. M. |first2=B. A. |last2=Alseikhan |first3=L. R. |last3=Jones |year=2000 |title=Localization and characterization of the calsequestrin-binding domain of triadin 1. Evidence for a charged beta-strand in mediating the protein-protein interaction |journal=J. Biol. Chem. |volume=275 |pages=17639–17646 |pmid=10748065 |doi=10.1074/jbc.M002091200}}</ref> The [[lumen (anatomy)|luminal]] (inner compartment of the sarcoplasmic reticulum) section of Triadin has areas of highly charged amino acid residues that act as luminal Ca<sup>2+</sup> receptors.<ref name="second" /><ref name="third" /><ref name="fifth" /> Triadin is also able to sense luminal Ca<sup>2+</sup> concentrations by mediating interactions between RYR2 and CASQ2.<ref name="fourth" /> Triadin has several [[isoform|different forms]]; Trisk 95 and Trisk 51, which are expressed in skeletal muscle, and Trisk 32 (CT1), which is mainly expressed in cardiac muscle.<ref>{{cite journal | last1 = Marty | first1 = I. | last2 = Fauré | first2 = J. | last3 = Fourest-Lieuvin | first3 = A. | last4 = Vassilopoulos | first4 = S. | last5 = Oddoux | first5 = S. | last6 = Brocard | first6 = J. | year = 2009 | title = Triadin: what possible function 20 years later? | url = http://jp.physoc.org/content/587/13/3117.full | journal = J. Physiol. | volume = 587 | issue = | pages = 3117–3121 | doi=10.1113/jphysiol.2009.171892}}</ref>
'''Triadin''', also known as '''TRDN''', is a human [[gene]]<ref name="entrez">{{cite web | title = Entrez Gene: TRDN triadin| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10345| accessdate = }}</ref> 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 different processing of the TRDN gene on [[chromosome 6]].<ref>{{cite journal |last=Thevenon |first=D. |last2=Smida-Rezgui |first2=S. |last3=Chevessier |first3=F. |last4=Groh |first4=S.|last5=Henry-Berger |first5=J. |last6=Romero |first6=N. B. |last7=Villaz |first7=M. |last8=De Waard |first8=M |last9=Marty |first9=I |year=2003 |title=Human skeletal muscle triadin: gene organization and cloning of the major isoform, Trisk 51 |journal=Biochem. Biophys. Res. Commun. |volume=303 |pages=669–675 |pmid=12659871 |issue=12 |doi=10.1016/s0006-291x(03)00406-6}}</ref> It is a transmembrane protein on the sarcoplasmic reticulum due to a well defined hydrophobic section<ref name="second">{{cite journal |last=Kobayashi |first=Y. M. |first2=L. R. |last2=Jones |year=1999 |title=Identification of triadin 1 as the predominant triadin isoform expressed in mammalian myocardium |journal=J. Biol. Chem. |volume=274 |pages=28660–28668 |pmid=10497235 |issue=40 |doi=10.1074/jbc.274.40.28660}}</ref><ref name="third">{{cite journal |last=Jones |first=L. R. |first2=L. |last2=Zhang |first3=K. |last3=Sanborn |first4=A. O. |last4=Jorgensen |first5=J. |last5=Kelley. |year=1995 |title=Purification, primary structure, and immunological characterization of the 26-kDa calsequestrin binding protein (junctin) from cardiac junctional sarcoplasmic reticulum |journal=J. Biol. Chem. |volume=270 |pages=30787–30796 |pmid=8530521 |issue=51 |doi=10.1074/jbc.270.51.30787}}</ref> and it forms a quaternary complex with the cardiac [[ryanodine receptor]] ([[RYR2]]), calsequestrin ([[CASQ2]]) and [[junctin]] proteins.<ref name="second" /><ref name="third" /><ref name="fourth">{{cite journal |last=Zhang |first=L. |first2=J. |last2=Kelley, |first3=G. |last3=Schmeisser, |first4=Y. M. |last4=Kobayashi |first5=L. R. |last5=Jones |year=1997 |title=Complex formation between junctin, triadin, calsequestrin, and the ryanodine receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane. |journal=J. Biol. Chem. |volume=272 |pages=23389–23397 |pmid=9287354 |doi=10.1074/jbc.272.37.23389}}</ref><ref name="fifth">{{cite journal |last=Kobayashi |first=Y. M. |first2=B. A. |last2=Alseikhan |first3=L. R. |last3=Jones |year=2000 |title=Localization and characterization of the calsequestrin-binding domain of triadin 1. Evidence for a charged beta-strand in mediating the protein-protein interaction |journal=J. Biol. Chem. |volume=275 |pages=17639–17646 |pmid=10748065 |doi=10.1074/jbc.M002091200}}</ref> The [[lumen (anatomy)|luminal]] (inner compartment of the sarcoplasmic reticulum) section of Triadin has areas of highly charged amino acid residues that act as luminal Ca<sup>2+</sup> receptors.<ref name="second" /><ref name="third" /><ref name="fifth" /> Triadin is also able to sense luminal Ca<sup>2+</sup> concentrations by mediating interactions between RYR2 and CASQ2.<ref name="fourth" /> Triadin has several [[isoform|different forms]]; Trisk 95 and Trisk 51, which are expressed in skeletal muscle, and Trisk 32 (CT1), which is mainly expressed in cardiac muscle.<ref>{{cite journal | last1 = Marty | first1 = I. | last2 = Fauré | first2 = J. | last3 = Fourest-Lieuvin | first3 = A. | last4 = Vassilopoulos | first4 = S. | last5 = Oddoux | first5 = S. | last6 = Brocard | first6 = J. | year = 2009 | title = Triadin: what possible function 20 years later? | url = http://jp.physoc.org/content/587/13/3117.full | journal = J. Physiol. | volume = 587 | issue = | pages = 3117–3121 | doi=10.1113/jphysiol.2009.171892}}</ref>


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TRDN has been shown to [[Protein-protein interaction|interact]] with [[RYR1]].<ref name=pmid14638677>{{cite journal |last=Lee |first=Jae Man |authorlink= |author2=Rho Seong-Hwan |author3=Shin Dong Wook |author4=Cho Chunghee |author5=Park Woo Jin |author6=Eom Soo Hyun |author7=Ma Jianjie |author8=Kim Do Han  |date=Feb 2004 |title=Negatively charged amino acids within the intraluminal loop of ryanodine receptor are involved in the interaction with triadin |journal=J. Biol. Chem. |volume=279 |issue=8 |pages=6994–7000 |publisher= |location = United States| issn = 0021-9258| pmid = 14638677 |doi = 10.1074/jbc.M312446200 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid9890886>{{cite journal |last=Caswell |first=A H |authorlink= |author2=Motoike H K |author3=Fan H |author4=Brandt N R  |date=Jan 1999 |title=Location of ryanodine receptor binding site on skeletal muscle triadin |journal=Biochemistry |volume=38 |issue=1 |pages=90–7 |publisher= |location = United States| issn = 0006-2960| pmid = 9890886 |doi =  10.1021/bi981306+| bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid7721813>{{cite journal |last=Guo |first=W |authorlink= |author2=Campbell K P  |date=Apr 1995 |title=Association of triadin with the ryanodine receptor and calsequestrin in the lumen of the sarcoplasmic reticulum |journal=J. Biol. Chem. |volume=270 |issue=16 |pages=9027–30 |publisher= |location = United States |issn = 0021-9258| pmid = 7721813 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = |doi=10.1074/jbc.270.16.9027 }}</ref><ref name=pmid10212196>{{cite journal |last=Groh |first=S |authorlink= |author2=Marty I |author3=Ottolia M |author4=Prestipino G |author5=Chapel A |author6=Villaz M |author7=Ronjat M  |date=Apr 1999 |title=Functional interaction of the cytoplasmic domain of triadin with the skeletal ryanodine receptor |journal=J. Biol. Chem. |volume=274 |issue=18 |pages=12278–83 |publisher= |location = United States |issn = 0021-9258| pmid = 10212196 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = |doi=10.1074/jbc.274.18.12278 }}</ref>
TRDN has been shown to [[Protein-protein interaction|interact]] with [[RYR1]].<ref name=pmid14638677>{{cite journal |last=Lee |first=Jae Man |authorlink= |author2=Rho Seong-Hwan |author3=Shin Dong Wook |author4=Cho Chunghee |author5=Park Woo Jin |author6=Eom Soo Hyun |author7=Ma Jianjie |author8=Kim Do Han  |date=Feb 2004 |title=Negatively charged amino acids within the intraluminal loop of ryanodine receptor are involved in the interaction with triadin |journal=J. Biol. Chem. |volume=279 |issue=8 |pages=6994–7000 |publisher= |location = United States| issn = 0021-9258| pmid = 14638677 |doi = 10.1074/jbc.M312446200 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid9890886>{{cite journal |last=Caswell |first=A H |authorlink= |author2=Motoike H K |author3=Fan H |author4=Brandt N R  |date=Jan 1999 |title=Location of ryanodine receptor binding site on skeletal muscle triadin |journal=Biochemistry |volume=38 |issue=1 |pages=90–7 |publisher= |location = United States| issn = 0006-2960| pmid = 9890886 |doi =  10.1021/bi981306+| bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = }}</ref><ref name=pmid7721813>{{cite journal |last=Guo |first=W |authorlink= |author2=Campbell K P  |date=Apr 1995 |title=Association of triadin with the ryanodine receptor and calsequestrin in the lumen of the sarcoplasmic reticulum |journal=J. Biol. Chem. |volume=270 |issue=16 |pages=9027–30 |publisher= |location = United States |issn = 0021-9258| pmid = 7721813 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = |doi=10.1074/jbc.270.16.9027 }}</ref><ref name=pmid10212196>{{cite journal |last=Groh |first=S |authorlink= |author2=Marty I |author3=Ottolia M |author4=Prestipino G |author5=Chapel A |author6=Villaz M |author7=Ronjat M  |date=Apr 1999 |title=Functional interaction of the cytoplasmic domain of triadin with the skeletal ryanodine receptor |journal=J. Biol. Chem. |volume=274 |issue=18 |pages=12278–83 |publisher= |location = United States |issn = 0021-9258| pmid = 10212196 | bibcode = | oclc =| id = | url = | language = | format = | accessdate = | laysummary = | laysource = | laydate = | quote = |doi=10.1074/jbc.274.18.12278 }}</ref>


Triadin is required to physically link the [[RYR2]] and CASQ2 proteins, so that RYR2 channel activity can be regulated by CASQ2.<ref name="seventh">{{cite journal |last=Gyorke |first=I. |last2=Hester |first2=N. |last3=Jones |first3=L. R. |last4=Gyorke |first4=S. |year=2004 |title=The Role of Calsequestrin, Triadin, and Junctin in Conferring Cardiac Ryanodine Receptor Responsiveness to Luminal Calcium |journal=Biophysical Journal |volume=86 |pages=2121–2128 |pmid=15041652 |doi=10.1016/S0006-3495(04)74271-X |pmc=1304063}}</ref> The linkage of RYR2 with CASQ2 occurs via highly charged luminal sections of Triadin<ref name="fifth" /> that are characterized as alternating positively and negatively charged amino acids, known as the KEKE motif.<ref name="third" /><ref name="fourth" /><ref name="fifth" /><ref>{{cite journal |last=Shin |first=D. W. |first2=J. |last2=Ma |first3=D. H. |last3=Kim |year=2000 |title=The asp-rich region at the carboxyl-terminus of calsequestrin binds to Ca<sup>2+</sup> and interacts with triadin |journal=FEBS Lett. |volume=486 |pages=178–182 |pmid=11113462 |doi=10.1016/S0014-5793(00)02246-8}}</ref>
Triadin is required to physically link the [[RYR2]] and CASQ2 proteins, so that RYR2 channel activity can be regulated by CASQ2.<ref name="seventh">{{cite journal |last=Gyorke |first=I. |last2=Hester |first2=N. |last3=Jones |first3=L. R. |last4=Gyorke |first4=S. |year=2004 |title=The Role of Calsequestrin, Triadin, and Junctin in Conferring Cardiac Ryanodine Receptor Responsiveness to Luminal Calcium |journal=Biophysical Journal |volume=86 |pages=2121–2128 |pmid=15041652 |doi=10.1016/S0006-3495(04)74271-X |pmc=1304063|bibcode=2004BpJ....86.2121G }}</ref> The linkage of RYR2 with CASQ2 occurs via highly charged luminal sections of Triadin<ref name="fifth" /> that are characterized as alternating positively and negatively charged amino acids, known as the KEKE motif.<ref name="third" /><ref name="fourth" /><ref name="fifth" /><ref>{{cite journal |last=Shin |first=D. W. |first2=J. |last2=Ma |first3=D. H. |last3=Kim |year=2000 |title=The asp-rich region at the carboxyl-terminus of calsequestrin binds to Ca<sup>2+</sup> and interacts with triadin |journal=FEBS Lett. |volume=486 |pages=178–182 |pmid=11113462 |doi=10.1016/S0014-5793(00)02246-8}}</ref>


[[Lumen (anatomy)|Luminal]] concentration levels of Ca<sup>2+</sup> are sensed by CSQ, and this information is transmitted to [[ryanodine|RyR]] via Triadin. At low luminal Ca<sup>2+</sup> concentrations, Triadin is bound to both RYR2 and CASQ2, so that CSQ prevents RYR2 from opening. At high luminal Ca<sup>2+</sup> concentrations, Ca<sup>2+</sup> binding sites on CASQ2 become occupied with Ca<sup>2+</sup>, leading to a weakened interaction between CASQ2 and Triadin. This removes CASQ2’s ability to have an inhibitory effect on the RYR2 channel activity. As more Ca<sup>2+</sup> binding sites on CASQ2 become occupied, there is an increasing probability of the RYR2 channel being able to open. Eventually, CASQ2 completely dissociates from Triadin and the RYR2 channel becomes completely uninhibited, although Triadin remains bound to RYR2 at all luminal concentrations of Ca<sup>2+</sup>.<ref name="seventh" />
[[Lumen (anatomy)|Luminal]] concentration levels of Ca<sup>2+</sup> are sensed by CSQ, and this information is transmitted to [[ryanodine|RyR]] via Triadin. At low luminal Ca<sup>2+</sup> concentrations, Triadin is bound to both RYR2 and CASQ2, so that CSQ prevents RYR2 from opening. At high luminal Ca<sup>2+</sup> concentrations, Ca<sup>2+</sup> binding sites on CASQ2 become occupied with Ca<sup>2+</sup>, leading to a weakened interaction between CASQ2 and Triadin. This removes CASQ2’s ability to have an inhibitory effect on the RYR2 channel activity. As more Ca<sup>2+</sup> binding sites on CASQ2 become occupied, there is an increasing probability of the RYR2 channel being able to open. Eventually, CASQ2 completely dissociates from Triadin and the RYR2 channel becomes completely uninhibited, although Triadin remains bound to RYR2 at all luminal concentrations of Ca<sup>2+</sup>.<ref name="seventh" />


==Relation to catecholaminergic polymorphic ventricular tachycardia==
==Relation to catecholaminergic polymorphic ventricular tachycardia==
Most mutations that result in [[CPVT]] are found in RYR2 or CASQ2 genes, however a third of CPVT patients have no mutations in either of these proteins, making a mutation in Triadin the most likely cause<ref name="ninth">{{cite journal |last=Roux-Buisson |first=N. |author2=Cacheux, M. |author3=Fourest-Lieuvin, A. |author4=Fauconnier, J. |author5=Brocard, J. |author6=Denjoy, I. |author7=Durand, P. |author8=Guicheney, P. |author9=Kyndt, F. |author10=Leenhardt, A. |author11=Le Marec, H. |author12=Lucet, V. |author13=Mabo, P. |author14=Probst, V. |author15=Monnier, N. |author16=Ray, P. F. |author17=Santoni, E. |author18=Tremeaux, P. |author19=Lacampagne, A. |author20=Faure, J. |author21=Lunardi, J. |author22=Marty, I. |year=2012 |title=Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human |journal=Human Molecular Genetics |volume=21 |pages=2759–2767 |pmid=22422768 |doi=10.1093/hmg/dds104 |pmc=3363337}}</ref> Because Triadin is necessary in the regulation of Ca<sup>2+</sup> release by the RyR channel during cardiac contraction, a mutation that prevents Triadin from being formed will make CASQ2 unable to inhibit the RYR2 channel activity, allowing Ca<sup>2+</sup> leaks and the development of [[CPVT]].<ref name="ninth" />
Most mutations that result in [[CPVT]] are found in RYR2 or CASQ2 genes, however a third of CPVT patients have no mutations in either of these proteins, making a mutation in Triadin the most likely cause<ref name="ninth">{{cite journal |last=Roux-Buisson |first=N. |author2=Cacheux, M. |author3=Fourest-Lieuvin, A. |author4=Fauconnier, J. |author5=Brocard, J. |author6=Denjoy, I. |author7=Durand, P. |author8=Guicheney, P. |author9=Kyndt, F. |author10=Leenhardt, A. |author11=Le Marec, H. |author12=Lucet, V. |author13=Mabo, P. |author14=Probst, V. |author15=Monnier, N. |author16=Ray, P. F. |author17=Santoni, E. |author18=Tremeaux, P. |author19=Lacampagne, A. |author20=Faure, J. |author21=Lunardi, J. |author22=Marty, I. |year=2012 |title=Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human |journal=Human Molecular Genetics |volume=21 |pages=2759–2767 |pmid=22422768 |doi=10.1093/hmg/dds104 |pmc=3363337|url=http://www.hal.inserm.fr/inserm-00763211/document }}</ref> Because Triadin is necessary in the regulation of Ca<sup>2+</sup> release by the RyR channel during cardiac contraction, a mutation that prevents Triadin from being formed will make CASQ2 unable to inhibit the RYR2 channel activity, allowing Ca<sup>2+</sup> leaks and the development of [[CPVT]].<ref name="ninth" />


A deletion of [[amino acids]] in the TRDN gene can result in an early [[stop codon]].<ref name="ninth" /> A premature [[stop codon]] can either prevent the [[gene]] from being translated into the Triadin protein, or can result in a shortened, nonfunctional Triadin protein.<ref name="ninth" /> A replacement of the amino acid [[Arginine]] for the amino acid [[Threonine]] at position 59 of the TRDN gene (pT59R) causes instability of Triadin, leading to degradation of the protein.<ref name="ninth" /> Any of these naturally occurring mutations result in an absence of functional Triadin protein, resulting in CPVT in patients.<ref name="ninth" />
A deletion of [[amino acids]] in the TRDN gene can result in an early [[stop codon]].<ref name="ninth" /> A premature [[stop codon]] can either prevent the [[gene]] from being translated into the Triadin protein, or can result in a shortened, nonfunctional Triadin protein.<ref name="ninth" /> A replacement of the amino acid [[Arginine]] for the amino acid [[Threonine]] at position 59 of the TRDN gene (pT59R) causes instability of Triadin, leading to degradation of the protein.<ref name="ninth" /> Any of these naturally occurring mutations result in an absence of functional Triadin protein, resulting in CPVT in patients.<ref name="ninth" />
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*{{cite journal |vauthors=Lee HG, Kang H, Kim DH, Park WJ |title=Interaction of HRC (histidine-rich Ca<sup>2+</sup>-binding protein) and triadin in the lumen of sarcoplasmic reticulum |journal=J. Biol. Chem. |volume=276 |issue= 43 |pages= 39533–8 |year= 2001 |pmid= 11504710 |doi= 10.1074/jbc.M010664200 }}
*{{cite journal |vauthors=Lee HG, Kang H, Kim DH, Park WJ |title=Interaction of HRC (histidine-rich Ca<sup>2+</sup>-binding protein) and triadin in the lumen of sarcoplasmic reticulum |journal=J. Biol. Chem. |volume=276 |issue= 43 |pages= 39533–8 |year= 2001 |pmid= 11504710 |doi= 10.1074/jbc.M010664200 }}
*{{cite journal | author=Hong CS |title=Molecular cloning and characterization of mouse cardiac triadin isoforms |journal=Gene |volume=278 |issue= 1–2 |pages= 193–9 |year= 2002 |pmid= 11707337 |doi=10.1016/S0378-1119(01)00718-1 |name-list-format=vanc| author2=Ji JH | author3=Kim JP | display-authors=3 | last4=Jung | first4=DH | last5=Kim | first5=DH }}
*{{cite journal | author=Hong CS |title=Molecular cloning and characterization of mouse cardiac triadin isoforms |journal=Gene |volume=278 |issue= 1–2 |pages= 193–9 |year= 2002 |pmid= 11707337 |doi=10.1016/S0378-1119(01)00718-1 |name-list-format=vanc| author2=Ji JH | author3=Kim JP | display-authors=3 | last4=Jung | first4=DH | last5=Kim | first5=DH }}
*{{cite journal | author=Strausberg RL |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |name-list-format=vanc| author2=Feingold EA | author3=Grouse LH | display-authors=3 | last4=Derge | first4=JG | last5=Klausner | first5=RD | last6=Collins | first6=FS | last7=Wagner | first7=L | last8=Shenmen | first8=CM | last9=Schuler | first9=GD }}
*{{cite journal | author=Strausberg RL |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 | pmc=139241 |name-list-format=vanc| author2=Feingold EA | author3=Grouse LH | display-authors=3 | last4=Derge | first4=JG | last5=Klausner | first5=RD | last6=Collins | first6=FS | last7=Wagner | first7=L | last8=Shenmen | first8=CM | last9=Schuler | first9=GD |bibcode=2002PNAS...9916899M }}
*{{cite journal | author=Kim E |title=Increased Ca<sup>2+</sup> storage capacity in the sarcoplasmic reticulum by overexpression of HRC (histidine-rich Ca<sup>2+</sup> binding protein) |journal=Biochem. Biophys. Res. Commun. |volume=300 |issue= 1 |pages= 192–6 |year= 2003 |pmid= 12480542 |doi=10.1016/S0006-291X(02)02829-2 |name-list-format=vanc| author2=Shin DW | author3=Hong CS | display-authors=3 | last4=Jeong | first4=Dongtak | last5=Kim | first5=Do Han | last6=Park | first6=Woo Jin }}
*{{cite journal | author=Kim E |title=Increased Ca<sup>2+</sup> storage capacity in the sarcoplasmic reticulum by overexpression of HRC (histidine-rich Ca<sup>2+</sup> binding protein) |journal=Biochem. Biophys. Res. Commun. |volume=300 |issue= 1 |pages= 192–6 |year= 2003 |pmid= 12480542 |doi=10.1016/S0006-291X(02)02829-2 |name-list-format=vanc| author2=Shin DW | author3=Hong CS | display-authors=3 | last4=Jeong | first4=Dongtak | last5=Kim | first5=Do Han | last6=Park | first6=Woo Jin }}
*{{cite journal | author=Thevenon D |title=Human skeletal muscle triadin: gene organization and cloning of the major isoform, Trisk 51 |journal=Biochem. Biophys. Res. Commun. |volume=303 |issue= 2 |pages= 669–75 |year= 2003 |pmid= 12659871 |doi=10.1016/S0006-291X(03)00406-6 |name-list-format=vanc| author2=Smida-Rezgui S | author3=Chevessier F | display-authors=3 | last4=Groh | first4=Séverine | last5=Henry-Berger | first5=Joëlle | last6=Beatriz Romero | first6=Norma | last7=Villaz | first7=Michel | last8=Dewaard | first8=Michel | last9=Marty | first9=Isabelle }}
*{{cite journal | author=Thevenon D |title=Human skeletal muscle triadin: gene organization and cloning of the major isoform, Trisk 51 |journal=Biochem. Biophys. Res. Commun. |volume=303 |issue= 2 |pages= 669–75 |year= 2003 |pmid= 12659871 |doi=10.1016/S0006-291X(03)00406-6 |name-list-format=vanc| author2=Smida-Rezgui S | author3=Chevessier F | display-authors=3 | last4=Groh | first4=Séverine | last5=Henry-Berger | first5=Joëlle | last6=Beatriz Romero | first6=Norma | last7=Villaz | first7=Michel | last8=Dewaard | first8=Michel | last9=Marty | first9=Isabelle }}

Latest revision as of 13:08, 4 November 2018

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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Ensembl

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UniProt

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RefSeq (mRNA)

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Triadin, also known as TRDN, is a human gene[1] 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 different processing of the TRDN gene on chromosome 6.[2] It is a transmembrane protein on the sarcoplasmic reticulum due to a well defined hydrophobic section[3][4] and it forms a quaternary complex with the cardiac ryanodine receptor (RYR2), calsequestrin (CASQ2) and junctin proteins.[3][4][5][6] The luminal (inner compartment of the sarcoplasmic reticulum) section of Triadin has areas of highly charged amino acid residues that act as luminal Ca2+ receptors.[3][4][6] Triadin is also able to sense luminal Ca2+ concentrations by mediating interactions between RYR2 and CASQ2.[5] Triadin has several different forms; Trisk 95 and Trisk 51, which are expressed in skeletal muscle, and Trisk 32 (CT1), which is mainly expressed in cardiac muscle.[7]


Interactions

TRDN has been shown to interact with RYR1.[8][9][10][11]

Triadin is required to physically link the RYR2 and CASQ2 proteins, so that RYR2 channel activity can be regulated by CASQ2.[12] The linkage of RYR2 with CASQ2 occurs via highly charged luminal sections of Triadin[6] that are characterized as alternating positively and negatively charged amino acids, known as the KEKE motif.[4][5][6][13]

Luminal concentration levels of Ca2+ are sensed by CSQ, and this information is transmitted to RyR via Triadin. At low luminal Ca2+ concentrations, Triadin is bound to both RYR2 and CASQ2, so that CSQ prevents RYR2 from opening. At high luminal Ca2+ concentrations, Ca2+ binding sites on CASQ2 become occupied with Ca2+, leading to a weakened interaction between CASQ2 and Triadin. This removes CASQ2’s ability to have an inhibitory effect on the RYR2 channel activity. As more Ca2+ binding sites on CASQ2 become occupied, there is an increasing probability of the RYR2 channel being able to open. Eventually, CASQ2 completely dissociates from Triadin and the RYR2 channel becomes completely uninhibited, although Triadin remains bound to RYR2 at all luminal concentrations of Ca2+.[12]

Relation to catecholaminergic polymorphic ventricular tachycardia

Most mutations that result in CPVT are found in RYR2 or CASQ2 genes, however a third of CPVT patients have no mutations in either of these proteins, making a mutation in Triadin the most likely cause[14] Because Triadin is necessary in the regulation of Ca2+ release by the RyR channel during cardiac contraction, a mutation that prevents Triadin from being formed will make CASQ2 unable to inhibit the RYR2 channel activity, allowing Ca2+ leaks and the development of CPVT.[14]

A deletion of amino acids in the TRDN gene can result in an early stop codon.[14] A premature stop codon can either prevent the gene from being translated into the Triadin protein, or can result in a shortened, nonfunctional Triadin protein.[14] A replacement of the amino acid Arginine for the amino acid Threonine at position 59 of the TRDN gene (pT59R) causes instability of Triadin, leading to degradation of the protein.[14] Any of these naturally occurring mutations result in an absence of functional Triadin protein, resulting in CPVT in patients.[14]

References

  1. ↑ "Entrez Gene: TRDN triadin".
  2. ↑ Thevenon, D.; Smida-Rezgui, S.; Chevessier, F.; Groh, S.; Henry-Berger, J.; Romero, N. B.; Villaz, M.; De Waard, M; Marty, I (2003). "Human skeletal muscle triadin: gene organization and cloning of the major isoform, Trisk 51". Biochem. Biophys. Res. Commun. 303 (12): 669–675. doi:10.1016/s0006-291x(03)00406-6. PMID 12659871.
  3. ↑ 3.0 3.1 3.2 Kobayashi, Y. M.; Jones, L. R. (1999). "Identification of triadin 1 as the predominant triadin isoform expressed in mammalian myocardium". J. Biol. Chem. 274 (40): 28660–28668. doi:10.1074/jbc.274.40.28660. PMID 10497235.
  4. ↑ 4.0 4.1 4.2 4.3 Jones, L. R.; Zhang, L.; Sanborn, K.; Jorgensen, A. O.; Kelley., J. (1995). "Purification, primary structure, and immunological characterization of the 26-kDa calsequestrin binding protein (junctin) from cardiac junctional sarcoplasmic reticulum". J. Biol. Chem. 270 (51): 30787–30796. doi:10.1074/jbc.270.51.30787. PMID 8530521.
  5. ↑ 5.0 5.1 5.2 Zhang, L.; Kelley,, J.; Schmeisser,, G.; Kobayashi, Y. M.; Jones, L. R. (1997). "Complex formation between junctin, triadin, calsequestrin, and the ryanodine receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane". J. Biol. Chem. 272: 23389–23397. doi:10.1074/jbc.272.37.23389. PMID 9287354.
  6. ↑ 6.0 6.1 6.2 6.3 Kobayashi, Y. M.; Alseikhan, B. A.; Jones, L. R. (2000). "Localization and characterization of the calsequestrin-binding domain of triadin 1. Evidence for a charged beta-strand in mediating the protein-protein interaction". J. Biol. Chem. 275: 17639–17646. doi:10.1074/jbc.M002091200. PMID 10748065.
  7. ↑ Marty, I.; Fauré, J.; Fourest-Lieuvin, A.; Vassilopoulos, S.; Oddoux, S.; Brocard, J. (2009). "Triadin: what possible function 20 years later?". J. Physiol. 587: 3117–3121. doi:10.1113/jphysiol.2009.171892.
  8. ↑ Lee, Jae Man; Rho Seong-Hwan; Shin Dong Wook; Cho Chunghee; Park Woo Jin; Eom Soo Hyun; Ma Jianjie; Kim Do Han (Feb 2004). "Negatively charged amino acids within the intraluminal loop of ryanodine receptor are involved in the interaction with triadin". J. Biol. Chem. United States. 279 (8): 6994–7000. doi:10.1074/jbc.M312446200. ISSN 0021-9258. PMID 14638677.
  9. ↑ Caswell, A H; Motoike H K; Fan H; Brandt N R (Jan 1999). "Location of ryanodine receptor binding site on skeletal muscle triadin". Biochemistry. United States. 38 (1): 90–7. doi:10.1021/bi981306+. ISSN 0006-2960. PMID 9890886.
  10. ↑ Guo, W; Campbell K P (Apr 1995). "Association of triadin with the ryanodine receptor and calsequestrin in the lumen of the sarcoplasmic reticulum". J. Biol. Chem. United States. 270 (16): 9027–30. doi:10.1074/jbc.270.16.9027. ISSN 0021-9258. PMID 7721813.
  11. ↑ Groh, S; Marty I; Ottolia M; Prestipino G; Chapel A; Villaz M; Ronjat M (Apr 1999). "Functional interaction of the cytoplasmic domain of triadin with the skeletal ryanodine receptor". J. Biol. Chem. United States. 274 (18): 12278–83. doi:10.1074/jbc.274.18.12278. ISSN 0021-9258. PMID 10212196.
  12. ↑ 12.0 12.1 Gyorke, I.; Hester, N.; Jones, L. R.; Gyorke, S. (2004). "The Role of Calsequestrin, Triadin, and Junctin in Conferring Cardiac Ryanodine Receptor Responsiveness to Luminal Calcium". Biophysical Journal. 86: 2121–2128. Bibcode:2004BpJ....86.2121G. doi:10.1016/S0006-3495(04)74271-X. PMC 1304063. PMID 15041652.
  13. ↑ Shin, D. W.; Ma, J.; Kim, D. H. (2000). "The asp-rich region at the carboxyl-terminus of calsequestrin binds to Ca2+ and interacts with triadin". FEBS Lett. 486: 178–182. doi:10.1016/S0014-5793(00)02246-8. PMID 11113462.
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 Roux-Buisson, N.; Cacheux, M.; Fourest-Lieuvin, A.; Fauconnier, J.; Brocard, J.; Denjoy, I.; Durand, P.; Guicheney, P.; Kyndt, F.; Leenhardt, A.; Le Marec, H.; Lucet, V.; Mabo, P.; Probst, V.; Monnier, N.; Ray, P. F.; Santoni, E.; Tremeaux, P.; Lacampagne, A.; Faure, J.; Lunardi, J.; Marty, I. (2012). "Absence of triadin, a protein of the calcium release complex, is responsible for cardiac arrhythmia with sudden death in human". Human Molecular Genetics. 21: 2759–2767. doi:10.1093/hmg/dds104. PMC 3363337. PMID 22422768.

Further reading

  • Taske NL, Eyre HJ, O'Brien RO, et al. (1995). "Molecular cloning of the cDNA encoding human skeletal muscle triadin and its localisation to chromosome 6q22-6q23". Eur. J. Biochem. 233 (1): 258–65. doi:10.1111/j.1432-1033.1995.258_1.x. PMID 7588753.
  • Guo W, Campbell KP (1995). "Association of triadin with the ryanodine receptor and calsequestrin in the lumen of the sarcoplasmic reticulum". J. Biol. Chem. 270 (16): 9027–30. doi:10.1074/jbc.270.16.9027. PMID 7721813.
  • Zhang L, Kelley J, Schmeisser G, et al. (1997). "Complex formation between junctin, triadin, calsequestrin, and the ryanodine receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane". J. Biol. Chem. 272 (37): 23389–97. doi:10.1074/jbc.272.37.23389. PMID 9287354.
  • Caswell AH, Motoike HK, Fan H, Brandt NR (1999). "Location of ryanodine receptor binding site on skeletal muscle triadin". Biochemistry. 38 (1): 90–7. doi:10.1021/bi981306+. PMID 9890886.
  • Groh S, Marty I, Ottolia M, et al. (1999). "Functional interaction of the cytoplasmic domain of triadin with the skeletal ryanodine receptor". J. Biol. Chem. 274 (18): 12278–83. doi:10.1074/jbc.274.18.12278. PMID 10212196.
  • Sacchetto R, Turcato F, Damiani E, Margreth A (1999). "Interaction of triadin with histidine-rich Ca2+-binding protein at the triadic junction in skeletal muscle fibers". J. Muscle Res. Cell. Motil. 20 (4): 403–15. doi:10.1023/A:1005580609414. PMID 10531621.
  • Kobayashi YM, Alseikhan BA, Jones LR (2000). "Localization and characterization of the calsequestrin-binding domain of triadin 1. Evidence for a charged beta-strand in mediating the protein-protein interaction". J. Biol. Chem. 275 (23): 17639–46. doi:10.1074/jbc.M002091200. PMID 10748065.
  • Kirchhefer U, Neumann J, Baba HA, et al. (2001). "Cardiac hypertrophy and impaired relaxation in transgenic mice overexpressing triadin 1". J. Biol. Chem. 276 (6): 4142–9. doi:10.1074/jbc.M006443200. PMID 11069905.
  • Shin DW, Ma J, Kim DH (2001). "The asp-rich region at the carboxyl-terminus of calsequestrin binds to Ca2+ and interacts with triadin". FEBS Lett. 486 (2): 178–82. doi:10.1016/S0014-5793(00)02246-8. PMID 11113462.
  • Lee HG, Kang H, Kim DH, Park WJ (2001). "Interaction of HRC (histidine-rich Ca2+-binding protein) and triadin in the lumen of sarcoplasmic reticulum". J. Biol. Chem. 276 (43): 39533–8. doi:10.1074/jbc.M010664200. PMID 11504710.
  • Hong CS, Ji JH, Kim JP, et al. (2002). "Molecular cloning and characterization of mouse cardiac triadin isoforms". Gene. 278 (1–2): 193–9. doi:10.1016/S0378-1119(01)00718-1. PMID 11707337.
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
  • Kim E, Shin DW, Hong CS, et al. (2003). "Increased Ca2+ storage capacity in the sarcoplasmic reticulum by overexpression of HRC (histidine-rich Ca2+ binding protein)". Biochem. Biophys. Res. Commun. 300 (1): 192–6. doi:10.1016/S0006-291X(02)02829-2. PMID 12480542.
  • Thevenon D, Smida-Rezgui S, Chevessier F, et al. (2003). "Human skeletal muscle triadin: gene organization and cloning of the major isoform, Trisk 51". Biochem. Biophys. Res. Commun. 303 (2): 669–75. doi:10.1016/S0006-291X(03)00406-6. PMID 12659871.
  • Lee JM, Rho SH, Shin DW, et al. (2004). "Negatively charged amino acids within the intraluminal loop of ryanodine receptor are involved in the interaction with triadin". J. Biol. Chem. 279 (8): 6994–7000. doi:10.1074/jbc.M312446200. PMID 14638677.
  • Olsen JV, Blagoev B, Gnad F, et al. (2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
  • Arvanitis DA, Vafiadaki E, Fan GC, et al. (2007). "Histidine-rich Ca-binding protein interacts with sarcoplasmic reticulum Ca-ATPase". Am. J. Physiol. Heart Circ. Physiol. 293 (3): H1581–9. doi:10.1152/ajpheart.00278.2007. PMID 17526652.

External links


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