NIH Public Access Author Manuscript J Cardiol Clin Res. Author manuscript; available in PMC 2014 April 12.
NIH-PA Author Manuscript
Published in final edited form as: J Cardiol Clin Res. ; 1(2): 1011–.
Xin Scaffolding Proteins and Arrhythmias Qinchuan Wang and Jim Jung-Ching Lin* Department of Biology, University of Iowa, USA
Keywords Xin repeat-containing protein; Intercalated disc; Cardiomyopathy; Arrhythmias; Ion channel surface expression
NIH-PA Author Manuscript
Intercalated disc (ICD), a unique specialized structure in cardiac muscle, transmits mechanical force and electrical impulses among cardiomyocytes. Recent studies also suggest that ICD, via scaffolding/anchoring proteins, can spatially organize and maintain key ion channel assemblies required for controlling the cardiac action potential. Defects in these processes can lead to arrhythmias and cardiac sudden death. For example, human Nav1.5 E1053K missense mutation disrupts its binding to ankyrin G, a scaffolding protein required for targeting Nav1.5 to ICD and transverse (T) tubule/lateral membranes of cardiomyocytes. As a consequence, this mutation causes Brugada syndrome [1]. Conversely, ankyrin G-deficient cardiomyocytes show reduced Nav1.5 surface expression and localization as well as reduced INa current density [2]. These findings clearly demonstrate a link between ankyrin G (a scaffolding protein) dysfunction and human arrhythmias. Another scaffolding protein, synapse-associated protein 97 (SAP97), a member of membraneassociated guanylate kinase (MAGUK) family, is preferentially localized to the ICDs and responsible for anchoring the pool of Nav1.5 to the ICDs through its PDZ domain interacting with the 3 last residues (Ser-Ile- Val) of Nav1.5 [3]. Thus, the question remaining to be addressed is whether the roles of these scaffolding proteins in targeting and maintaining Nav1.5 to the ICD membrane are complementary, cooperative, competitive or redundant.
NIH-PA Author Manuscript
In addition to Nav1.5, Kv4.2/Kv4.3 (α-subunit of transient outward K+ channel, Ito,f) and Kv1.5 and Kcne2 (α-subunit and transmembrane ancillary-subunit, respectively, of delayed K+ rectifier, Ik,slow1, in mouse) are reported to be associated with ICD and T-tubule/lateral membranes [4–6]. Interestingly, SAP97 also interacts with the 3 last residues of Kv4.2/4.3 (Ser-Ala-Leu) and Kv1.5 (Thr-Asp-Val) to potentially target and/or anchor ion channels to cell surface [6–8]. However, the molecular mechanisms underlying the targeting and maintaining of these channel assemblies to ICD membrane remain unclear. In cardiac diseases, Ito,f and Ik,slow1 are often altered, thus contributing to the risk of arrhythmias and cardiac sudden death. Three recent publications together have addressed that a novel scaffolding protein family, Xin, may play important roles in targeting and/ or maintaining Ito,f and Ik,slow1 channels to the ICDs [5,9,10]. The Xin family of proteins was originally identified to contain 15~28 repeats of the 16-amino acid residues (termed the Xin repeats), which are responsible for binding and bundling actin filaments, and a conserved β-catenin binding domain, which is responsible for localizing Xin to the adherens junction of the ICD [11,12]. The mouse Xin genes (mXinα and mXinβ) are orthologs of human cardiomyopathyCopyright © 2013 Lin et al. Corresponding author: Jim Jung-Ching Lin, Department of Biology University of Iowa, 340 Biology Building East 210 E. Iowa Avenue, Iowa City, IA 52242, USA, Tel: 319-335-1075; Fax: 319-353-2275; [email protected].
Wang and Lin
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NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
associated genes (CMYA1 and CMYA3, respectively). The human Xin (hXinα and hXinβ) proteins are also called Xin actin-binding repeat containing protein 1 and 2 (XIRP1 and 2), respectively [13]. Ablation of mXinα in mice leads to late-onset cardiomyopathy with conduction defects [14,15]. Electrophysiological studies on cardiomyocytes prepared from juvenile mice revealed that such conduction defects were likely due to depressions in both Ito and Ik current density in mutant cardiomyocytes [9]. These reductions would slow down the repolarization process, leading to the observations of prolonged action potential duration and higher incidence of EAD (early after depolarization) in mXinα-null cells [9]. Similar EAD has been frequently detected in cardiomyocytes from patients with long QT syndrome, hypokalemia, class III antiarrhythmic agent treatments or failing hearts [16]. Yeast 2 hybrid assays further identified KChIP2, filamin and p120-catenin as mXinα-interacting partners [9,11]. KChIP2 is a cytoplasmic ancillary subunit of Ito,f channel assembly and can quantitatively regulate Ito,f channel activity. The KChIP2-null mice completely lose Ito,f and are highly susceptible to the induction of cardiac arrhythmias [17]. The facts that mXinα directly interacts with KChIP2 and filamin and that mXinα-null cardiomyocytes have a reduced Ito current density suggest a novel role for mXinα in Ito,f channel surface expression. Consistent with this role, Chan et al (2011) have found a significant reduction of both KChIP2 and filamin but not Kv4.2/4.3 in the membrane fraction of the mXinα-null hearts [9]. Recent studies also implicate that mXinα participates in the surface expression of additional ion channels; both mXinα and Kv1.5, which regulates Ik,slow1, have been recently shown to associate with cortactin [5,10]. Cortactin is one of the key molecules involved in regulating cortical actin dynamics [18], whose activity may be critical for Ik,slow1 channel surface expression and localization. In mXinα-null cardiomyocytes, the ICD- localized population of cortactin is drastically reduced, whereas the other population of cortactin underneath the lateral membrane remains unaltered [10]. These findings suggest that mXinα may recruit or stabilize cortactin together with Kv1.5 to the ICDs. Consistent with this role, electrophysiological studies indicate that total Ik (including both Ik,slow1 and Ik,slow2) current density is depressed in mXinα-null cardiomyocytes [9]. In addition to showing the association of Kv1.5 with cortactin, Radice group used cardiac-specific N- cadherin conditional knockout mice to provide strong evidence for essential roles of N- cadherin in ICD integrity, cardiac conduction & rhythms, and Ik,slow1 surface expression [5,19–21]. Cardiac-specific loss of N-cadherin in mice leads to complete dissolution of the ICD structure, gap junction remodeling and slow conduction of ventricles. The mutant mice are more susceptible to arrhythmias and cardiac sudden death. Similar to mXinα-null cardiomyocytes, N-cadherin conditional knockout cells also display prolonged action potential duration at 75% and 90% repolarization, higher incidence of EAD, and attenuated Ik,slow1[5]. Unlike that in mXinα-null cardiomyocytes, the loss of N-cadherin in the heart results in a global reduction of cortactin at both ICD and lateral membranes [5], even though N-cadherin is known to be exclusively localized to the ICD. This global reduction of cortactin may be secondary to a cell shape change in N-cadherin conditional knockout cardiomyocytes due to the complete dissolution of the ICD structure. Coimmunoprecipitation with anti-cortactin or anti-N-cadherin did not reveal a direct association between cortactin and N-cadherin [5]. It is reasonable to hypothesize that Xin repeat-containing proteins may be required for this association. It is known that mXinα interacts not only with cortactin but also with p120-catenin [10] and β-catenin [11]. Both of catenins are important determinants for N-cadherin stability and function. Recently, mXinβ has been shown to be essential for the postnatal maturation of ICDs and for the localization of mXinα and N-cadherin to the ICDs [22,23]. Based on these converging lines of evidence, a compelling hypothesis is that mXinβ also plays a role in cardiac electrophysiology. Studies are currently underway in our laboratory to explore the roles of mXinβ in surface expression of ion channels and the intricate regulation of cardiomyocyte excitability. J Cardiol Clin Res. Author manuscript; available in PMC 2014 April 12.
Wang and Lin
Page 3
Acknowledgments NIH-PA Author Manuscript
We thank Dr. Chun-Fan Wu for critical reading and comments of the manuscript. This work was supported by NIH grant HL107383.
References
NIH-PA Author Manuscript NIH-PA Author Manuscript
1. Mohler PJ, Rivolta I, Napolitano C, LeMaillet G, Lambert S, Priori SG, et al. Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes. Proc Natl Acad Sci U S A. 2004; 101:17533–17538. [PubMed: 15579534] 2. Lowe JS, Palygin O, Bhasin N, Hund TJ, Boyden PA, Shibata E, et al. Voltage-gated Nav channel targeting in the heart requires an ankyrin-G dependent cellular pathway. J Cell Biol. 2008; 180:173– 186. [PubMed: 18180363] 3. Petitprez S, Zmoos AF, Ogrodnik J, Balse E, Raad N, El-Haou S, et al. SAP97 and dystrophin macromolecular complexes determine two pools of cardiac sodium channels Nav1.5 in cardiomyocytes. Circ Res. 2011; 108:294–304. [PubMed: 21164104] 4. Barry DM, Trimmer JS, Merlie JP, Nerbonne JM. Differential expression of voltage-gated K+ channel subunits in adult rat heart. Relation to functional K+ channels? Circ Res. 1995; 77:361–369. [PubMed: 7614722] 5. Cheng L, Yung A, Covarrubias M, Radice GL. Cortactin is required for N-cadherin regulation of Kv1.5 channel function. J Biol Chem. 2011; 286:20478–20489. [PubMed: 21507952] 6. El-Haou S, Balse E, Neyroud N, Dilanian G, Gavillet B, Abriel H, et al. Kv4 potassium channels form a tripartite complex with the anchoring protein SAP97 and CaMKII in cardiac myocytes. Circ Res. 2009; 104:758–769. [PubMed: 19213956] 7. Abi-Char J, El-Haou S, Balse E, Neyroud N, Vranckx R, Coulombe A, et al. The anchoring protein SAP97 retains Kv1.5 channels in the plasma membrane of cardiac myocytes. Am J Physiol Heart Circ Physiol. 2008; 294:H1851–1861. [PubMed: 18245566] 8. Murata M, Buckett PD, Zhou J, Brunner M, Folco E, Koren G. SAP97 interacts with Kv1.5 in heterologous expression systems. Am J Physiol Heart Circ Physiol. 2001; 281:H2575–2584. [PubMed: 11709425] 9. Chan FC, Cheng CP, Wu KH, Chen YC, Hsu CH, Gustafson-Wagner EA, et al. Intercalated discassociated protein, mXinα-α influences surface expression of ITO currents in ventricular myocytes. Front Biosci (Elite Ed). 2011; 3:1425–1442. [PubMed: 21622147] 10. Wang Q, Lu TL, Adams E, Lin JL, Lin JJ. Intercalated disc protein, mXinα, suppresses p120catenin-induced branching phenotype via its interactions with p120-catenin and cortactin. Arch Biochem Biophys. 2013; 535:91–100. [PubMed: 23296090] 11. Choi S, Gustafson-Wagner EA, Wang Q, Harlan SM, Sinn HW, Lin JL, et al. The intercalated disk protein, mXin alpha, is capable of interacting with beta-catenin and bundling actin filaments. J Biol Chem. 2007; 282:36024–36036. [PubMed: 17925400] 12. Pacholsky D, Vakeel P, Himmel M, Löwe T, Stradal T, Rottner K, et al. Xin repeats define a novel actin-binding motif. J Cell Sci. 2004; 117:5257–5268. [PubMed: 15454575] 13. Wang Q, Lin JL, Wu KH, Wang DZ, Reiter RS, Sinn HW, et al. Xin proteins and intercalated disc maturation, signaling and diseases. Front Biosci (Landmark Ed). 2012; 17:2566–2593. [PubMed: 22652799] 14. Gustafson-Wagner EA, Sinn HW, Chen YL, Wang DZ, Reiter RS, Lin JL, et al. Loss of mXinα, an intercalated disk protein, results in cardiac hypertrophy and cardiomyopathy with conduction defects. Am J Physiol Heart Circ Physiol. 2007; 293:H2680–2692. [PubMed: 17766470] 15. Otten J, van der Ven PF, Vakeel P, Eulitz S, Kirfel G, Brandau O, et al. Complete loss of murine Xin results in a mild cardiac phenotype with altered distribution of intercalated discs. Cardiovasc Res. 2010; 85:739–750. [PubMed: 19843512] 16. Pogwizd SM, Bers DM. Cellular basis of triggered arrhythmias in heart failure. Trends Cardiovasc Med. 2004; 14:61–66. [PubMed: 15030791]
J Cardiol Clin Res. Author manuscript; available in PMC 2014 April 12.
Wang and Lin
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NIH-PA Author Manuscript
17. Kuo HC, Cheng CF, Clark RB, Lin JJ, Lin JL, Hoshijima M, et al. A defect in the Kv channelinteracting protein 2 (KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventricular tachycardia. Cell. 2001; 107:801–813. [PubMed: 11747815] 18. Ammer AG, Weed SA. Cortactin branches out: roles in regulating protrusive actin dynamics. Cell Motil Cytoskeleton. 2008; 65:687–707. [PubMed: 18615630] 19. Kostetskii I, Li J, Xiong Y, Zhou R, Ferrari VA, Patel VV, et al. Induced deletion of the Ncadherin gene in the heart leads to dissolution of the intercalated disc structure. Circ Res. 2005; 96:346–354. [PubMed: 15662031] 20. Li J, Levin MD, Xiong Y, Petrenko N, Patel VV, Radice GL. N-cadherin haploinsufficiency affects cardiac gap junctions and arrhythmic susceptibility. J Mol Cell Cardiol. 2008; 44:597–606. [PubMed: 18201716] 21. Li J, Patel VV, Kostetskii I, Xiong Y, Chu AF, Jacobson JT, et al. Cardiac-specific loss of Ncadherin leads to alteration in connexins with conduction slowing and arrhythmogenesis. Circ Res. 2005; 97:474–481. [PubMed: 16100040] 22. Wang Q, Lin JL, Chan SY, Lin JJ. The Xin repeat-containing protein, mXinα, initiates the maturation of the intercalated discs during postnatal heart development. Dev Biol. 2013; 374:264– 280. [PubMed: 23261932] 23. Wang Q, Lin JL, Reinking BE, Feng HZ, Chan FC, Lin CI, et al. Essential roles of an intercalated disc protein, mXin beta, in postnatal heart growth and survival. Circ Res. 2010; 106:1468–1478. [PubMed: 20360251]
NIH-PA Author Manuscript NIH-PA Author Manuscript J Cardiol Clin Res. Author manuscript; available in PMC 2014 April 12.
NIH-PA Author Manuscript
Published in final edited form as: J Cardiol Clin Res. ; 1(2): 1011–.
Xin Scaffolding Proteins and Arrhythmias Qinchuan Wang and Jim Jung-Ching Lin* Department of Biology, University of Iowa, USA
Keywords Xin repeat-containing protein; Intercalated disc; Cardiomyopathy; Arrhythmias; Ion channel surface expression
NIH-PA Author Manuscript
Intercalated disc (ICD), a unique specialized structure in cardiac muscle, transmits mechanical force and electrical impulses among cardiomyocytes. Recent studies also suggest that ICD, via scaffolding/anchoring proteins, can spatially organize and maintain key ion channel assemblies required for controlling the cardiac action potential. Defects in these processes can lead to arrhythmias and cardiac sudden death. For example, human Nav1.5 E1053K missense mutation disrupts its binding to ankyrin G, a scaffolding protein required for targeting Nav1.5 to ICD and transverse (T) tubule/lateral membranes of cardiomyocytes. As a consequence, this mutation causes Brugada syndrome [1]. Conversely, ankyrin G-deficient cardiomyocytes show reduced Nav1.5 surface expression and localization as well as reduced INa current density [2]. These findings clearly demonstrate a link between ankyrin G (a scaffolding protein) dysfunction and human arrhythmias. Another scaffolding protein, synapse-associated protein 97 (SAP97), a member of membraneassociated guanylate kinase (MAGUK) family, is preferentially localized to the ICDs and responsible for anchoring the pool of Nav1.5 to the ICDs through its PDZ domain interacting with the 3 last residues (Ser-Ile- Val) of Nav1.5 [3]. Thus, the question remaining to be addressed is whether the roles of these scaffolding proteins in targeting and maintaining Nav1.5 to the ICD membrane are complementary, cooperative, competitive or redundant.
NIH-PA Author Manuscript
In addition to Nav1.5, Kv4.2/Kv4.3 (α-subunit of transient outward K+ channel, Ito,f) and Kv1.5 and Kcne2 (α-subunit and transmembrane ancillary-subunit, respectively, of delayed K+ rectifier, Ik,slow1, in mouse) are reported to be associated with ICD and T-tubule/lateral membranes [4–6]. Interestingly, SAP97 also interacts with the 3 last residues of Kv4.2/4.3 (Ser-Ala-Leu) and Kv1.5 (Thr-Asp-Val) to potentially target and/or anchor ion channels to cell surface [6–8]. However, the molecular mechanisms underlying the targeting and maintaining of these channel assemblies to ICD membrane remain unclear. In cardiac diseases, Ito,f and Ik,slow1 are often altered, thus contributing to the risk of arrhythmias and cardiac sudden death. Three recent publications together have addressed that a novel scaffolding protein family, Xin, may play important roles in targeting and/ or maintaining Ito,f and Ik,slow1 channels to the ICDs [5,9,10]. The Xin family of proteins was originally identified to contain 15~28 repeats of the 16-amino acid residues (termed the Xin repeats), which are responsible for binding and bundling actin filaments, and a conserved β-catenin binding domain, which is responsible for localizing Xin to the adherens junction of the ICD [11,12]. The mouse Xin genes (mXinα and mXinβ) are orthologs of human cardiomyopathyCopyright © 2013 Lin et al. Corresponding author: Jim Jung-Ching Lin, Department of Biology University of Iowa, 340 Biology Building East 210 E. Iowa Avenue, Iowa City, IA 52242, USA, Tel: 319-335-1075; Fax: 319-353-2275; [email protected].
Wang and Lin
Page 2
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
associated genes (CMYA1 and CMYA3, respectively). The human Xin (hXinα and hXinβ) proteins are also called Xin actin-binding repeat containing protein 1 and 2 (XIRP1 and 2), respectively [13]. Ablation of mXinα in mice leads to late-onset cardiomyopathy with conduction defects [14,15]. Electrophysiological studies on cardiomyocytes prepared from juvenile mice revealed that such conduction defects were likely due to depressions in both Ito and Ik current density in mutant cardiomyocytes [9]. These reductions would slow down the repolarization process, leading to the observations of prolonged action potential duration and higher incidence of EAD (early after depolarization) in mXinα-null cells [9]. Similar EAD has been frequently detected in cardiomyocytes from patients with long QT syndrome, hypokalemia, class III antiarrhythmic agent treatments or failing hearts [16]. Yeast 2 hybrid assays further identified KChIP2, filamin and p120-catenin as mXinα-interacting partners [9,11]. KChIP2 is a cytoplasmic ancillary subunit of Ito,f channel assembly and can quantitatively regulate Ito,f channel activity. The KChIP2-null mice completely lose Ito,f and are highly susceptible to the induction of cardiac arrhythmias [17]. The facts that mXinα directly interacts with KChIP2 and filamin and that mXinα-null cardiomyocytes have a reduced Ito current density suggest a novel role for mXinα in Ito,f channel surface expression. Consistent with this role, Chan et al (2011) have found a significant reduction of both KChIP2 and filamin but not Kv4.2/4.3 in the membrane fraction of the mXinα-null hearts [9]. Recent studies also implicate that mXinα participates in the surface expression of additional ion channels; both mXinα and Kv1.5, which regulates Ik,slow1, have been recently shown to associate with cortactin [5,10]. Cortactin is one of the key molecules involved in regulating cortical actin dynamics [18], whose activity may be critical for Ik,slow1 channel surface expression and localization. In mXinα-null cardiomyocytes, the ICD- localized population of cortactin is drastically reduced, whereas the other population of cortactin underneath the lateral membrane remains unaltered [10]. These findings suggest that mXinα may recruit or stabilize cortactin together with Kv1.5 to the ICDs. Consistent with this role, electrophysiological studies indicate that total Ik (including both Ik,slow1 and Ik,slow2) current density is depressed in mXinα-null cardiomyocytes [9]. In addition to showing the association of Kv1.5 with cortactin, Radice group used cardiac-specific N- cadherin conditional knockout mice to provide strong evidence for essential roles of N- cadherin in ICD integrity, cardiac conduction & rhythms, and Ik,slow1 surface expression [5,19–21]. Cardiac-specific loss of N-cadherin in mice leads to complete dissolution of the ICD structure, gap junction remodeling and slow conduction of ventricles. The mutant mice are more susceptible to arrhythmias and cardiac sudden death. Similar to mXinα-null cardiomyocytes, N-cadherin conditional knockout cells also display prolonged action potential duration at 75% and 90% repolarization, higher incidence of EAD, and attenuated Ik,slow1[5]. Unlike that in mXinα-null cardiomyocytes, the loss of N-cadherin in the heart results in a global reduction of cortactin at both ICD and lateral membranes [5], even though N-cadherin is known to be exclusively localized to the ICD. This global reduction of cortactin may be secondary to a cell shape change in N-cadherin conditional knockout cardiomyocytes due to the complete dissolution of the ICD structure. Coimmunoprecipitation with anti-cortactin or anti-N-cadherin did not reveal a direct association between cortactin and N-cadherin [5]. It is reasonable to hypothesize that Xin repeat-containing proteins may be required for this association. It is known that mXinα interacts not only with cortactin but also with p120-catenin [10] and β-catenin [11]. Both of catenins are important determinants for N-cadherin stability and function. Recently, mXinβ has been shown to be essential for the postnatal maturation of ICDs and for the localization of mXinα and N-cadherin to the ICDs [22,23]. Based on these converging lines of evidence, a compelling hypothesis is that mXinβ also plays a role in cardiac electrophysiology. Studies are currently underway in our laboratory to explore the roles of mXinβ in surface expression of ion channels and the intricate regulation of cardiomyocyte excitability. J Cardiol Clin Res. Author manuscript; available in PMC 2014 April 12.
Wang and Lin
Page 3
Acknowledgments NIH-PA Author Manuscript
We thank Dr. Chun-Fan Wu for critical reading and comments of the manuscript. This work was supported by NIH grant HL107383.
References
NIH-PA Author Manuscript NIH-PA Author Manuscript
1. Mohler PJ, Rivolta I, Napolitano C, LeMaillet G, Lambert S, Priori SG, et al. Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes. Proc Natl Acad Sci U S A. 2004; 101:17533–17538. [PubMed: 15579534] 2. Lowe JS, Palygin O, Bhasin N, Hund TJ, Boyden PA, Shibata E, et al. Voltage-gated Nav channel targeting in the heart requires an ankyrin-G dependent cellular pathway. J Cell Biol. 2008; 180:173– 186. [PubMed: 18180363] 3. Petitprez S, Zmoos AF, Ogrodnik J, Balse E, Raad N, El-Haou S, et al. SAP97 and dystrophin macromolecular complexes determine two pools of cardiac sodium channels Nav1.5 in cardiomyocytes. Circ Res. 2011; 108:294–304. [PubMed: 21164104] 4. Barry DM, Trimmer JS, Merlie JP, Nerbonne JM. Differential expression of voltage-gated K+ channel subunits in adult rat heart. Relation to functional K+ channels? Circ Res. 1995; 77:361–369. [PubMed: 7614722] 5. Cheng L, Yung A, Covarrubias M, Radice GL. Cortactin is required for N-cadherin regulation of Kv1.5 channel function. J Biol Chem. 2011; 286:20478–20489. [PubMed: 21507952] 6. El-Haou S, Balse E, Neyroud N, Dilanian G, Gavillet B, Abriel H, et al. Kv4 potassium channels form a tripartite complex with the anchoring protein SAP97 and CaMKII in cardiac myocytes. Circ Res. 2009; 104:758–769. [PubMed: 19213956] 7. Abi-Char J, El-Haou S, Balse E, Neyroud N, Vranckx R, Coulombe A, et al. The anchoring protein SAP97 retains Kv1.5 channels in the plasma membrane of cardiac myocytes. Am J Physiol Heart Circ Physiol. 2008; 294:H1851–1861. [PubMed: 18245566] 8. Murata M, Buckett PD, Zhou J, Brunner M, Folco E, Koren G. SAP97 interacts with Kv1.5 in heterologous expression systems. Am J Physiol Heart Circ Physiol. 2001; 281:H2575–2584. [PubMed: 11709425] 9. Chan FC, Cheng CP, Wu KH, Chen YC, Hsu CH, Gustafson-Wagner EA, et al. Intercalated discassociated protein, mXinα-α influences surface expression of ITO currents in ventricular myocytes. Front Biosci (Elite Ed). 2011; 3:1425–1442. [PubMed: 21622147] 10. Wang Q, Lu TL, Adams E, Lin JL, Lin JJ. Intercalated disc protein, mXinα, suppresses p120catenin-induced branching phenotype via its interactions with p120-catenin and cortactin. Arch Biochem Biophys. 2013; 535:91–100. [PubMed: 23296090] 11. Choi S, Gustafson-Wagner EA, Wang Q, Harlan SM, Sinn HW, Lin JL, et al. The intercalated disk protein, mXin alpha, is capable of interacting with beta-catenin and bundling actin filaments. J Biol Chem. 2007; 282:36024–36036. [PubMed: 17925400] 12. Pacholsky D, Vakeel P, Himmel M, Löwe T, Stradal T, Rottner K, et al. Xin repeats define a novel actin-binding motif. J Cell Sci. 2004; 117:5257–5268. [PubMed: 15454575] 13. Wang Q, Lin JL, Wu KH, Wang DZ, Reiter RS, Sinn HW, et al. Xin proteins and intercalated disc maturation, signaling and diseases. Front Biosci (Landmark Ed). 2012; 17:2566–2593. [PubMed: 22652799] 14. Gustafson-Wagner EA, Sinn HW, Chen YL, Wang DZ, Reiter RS, Lin JL, et al. Loss of mXinα, an intercalated disk protein, results in cardiac hypertrophy and cardiomyopathy with conduction defects. Am J Physiol Heart Circ Physiol. 2007; 293:H2680–2692. [PubMed: 17766470] 15. Otten J, van der Ven PF, Vakeel P, Eulitz S, Kirfel G, Brandau O, et al. Complete loss of murine Xin results in a mild cardiac phenotype with altered distribution of intercalated discs. Cardiovasc Res. 2010; 85:739–750. [PubMed: 19843512] 16. Pogwizd SM, Bers DM. Cellular basis of triggered arrhythmias in heart failure. Trends Cardiovasc Med. 2004; 14:61–66. [PubMed: 15030791]
J Cardiol Clin Res. Author manuscript; available in PMC 2014 April 12.
Wang and Lin
Page 4
NIH-PA Author Manuscript
17. Kuo HC, Cheng CF, Clark RB, Lin JJ, Lin JL, Hoshijima M, et al. A defect in the Kv channelinteracting protein 2 (KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventricular tachycardia. Cell. 2001; 107:801–813. [PubMed: 11747815] 18. Ammer AG, Weed SA. Cortactin branches out: roles in regulating protrusive actin dynamics. Cell Motil Cytoskeleton. 2008; 65:687–707. [PubMed: 18615630] 19. Kostetskii I, Li J, Xiong Y, Zhou R, Ferrari VA, Patel VV, et al. Induced deletion of the Ncadherin gene in the heart leads to dissolution of the intercalated disc structure. Circ Res. 2005; 96:346–354. [PubMed: 15662031] 20. Li J, Levin MD, Xiong Y, Petrenko N, Patel VV, Radice GL. N-cadherin haploinsufficiency affects cardiac gap junctions and arrhythmic susceptibility. J Mol Cell Cardiol. 2008; 44:597–606. [PubMed: 18201716] 21. Li J, Patel VV, Kostetskii I, Xiong Y, Chu AF, Jacobson JT, et al. Cardiac-specific loss of Ncadherin leads to alteration in connexins with conduction slowing and arrhythmogenesis. Circ Res. 2005; 97:474–481. [PubMed: 16100040] 22. Wang Q, Lin JL, Chan SY, Lin JJ. The Xin repeat-containing protein, mXinα, initiates the maturation of the intercalated discs during postnatal heart development. Dev Biol. 2013; 374:264– 280. [PubMed: 23261932] 23. Wang Q, Lin JL, Reinking BE, Feng HZ, Chan FC, Lin CI, et al. Essential roles of an intercalated disc protein, mXin beta, in postnatal heart growth and survival. Circ Res. 2010; 106:1468–1478. [PubMed: 20360251]
NIH-PA Author Manuscript NIH-PA Author Manuscript J Cardiol Clin Res. Author manuscript; available in PMC 2014 April 12.
