Dysfunction in the βiI spectrin-dependent cytoskeleton underlies human arrhythmia

Sakima A. Smith, Amy C. Sturm, Jerry Curran, Crystal F. Kline, Sean C. Little, Ingrid M. Bonilla, Victor P. Long, Michael Makara, Iuliia Polina, Langston D. Hughes, Tyler R. Webb, Zhiyi Wei, Patrick Wright, Niels Voigt, Deepak Bhakta, Katherine G. Spoonamore, Chuansheng Zhang, Raul Weiss, Philip F. Binkley, Paul M. Janssen & 11 others Ahmet Kilic, Robert S. Higgins, Mingzhai Sun, Jianjie Ma, Dobromir Dobrev, Mingjie Zhang, Cynthia A. Carnes, Matteo Vatta, Matthew N. Rasband, Thomas J. Hund, Peter J. Mohler

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background: The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked to cardiac pathologies, including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction and cardiac electric activity is not well understood and often overlooked in the cardiac arrhythmia field. Methods and Results: Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that βII spectrin, an actin-associated molecule, is essential for the posttranslational targeting and localization of critical membrane proteins in heart. βII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/βII spectrin interaction, leading to severe human arrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electric and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, βII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes, including the Na/Ca exchanger, ryanodine receptor 2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in βII spectrin-deficient mice. Conclusions: Our findings identify βII spectrin as critical for normal myocyte electric activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.

Original languageEnglish
Pages (from-to)695-708
Number of pages14
JournalCirculation
Volume131
Issue number8
DOIs
StatePublished - 2015

Fingerprint

Spectrin
Cytoskeleton
Cardiac Arrhythmias
Ankyrins
Phenotype
Muscle Cells
Actins
Membrane Proteins
Ryanodine Receptor Calcium Release Channel
Mutation
Cytoskeletal Proteins
Sarcoplasmic Reticulum
Muscular Diseases
Cardiac Myocytes
Heart Failure
Cell Membrane
Pathology
Calcium
Membranes
Health

Keywords

  • Arrhythmias
  • Cardiac
  • Catecholaminergic polymorphic ventricular arrhythmia
  • Cytoskeleton
  • Ion channels
  • Protein transport
  • Ventricular tachycardia

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Smith, S. A., Sturm, A. C., Curran, J., Kline, C. F., Little, S. C., Bonilla, I. M., ... Mohler, P. J. (2015). Dysfunction in the βiI spectrin-dependent cytoskeleton underlies human arrhythmia. Circulation, 131(8), 695-708. https://doi.org/10.1161/CIRCULATIONAHA.114.013708

Dysfunction in the βiI spectrin-dependent cytoskeleton underlies human arrhythmia. / Smith, Sakima A.; Sturm, Amy C.; Curran, Jerry; Kline, Crystal F.; Little, Sean C.; Bonilla, Ingrid M.; Long, Victor P.; Makara, Michael; Polina, Iuliia; Hughes, Langston D.; Webb, Tyler R.; Wei, Zhiyi; Wright, Patrick; Voigt, Niels; Bhakta, Deepak; Spoonamore, Katherine G.; Zhang, Chuansheng; Weiss, Raul; Binkley, Philip F.; Janssen, Paul M.; Kilic, Ahmet; Higgins, Robert S.; Sun, Mingzhai; Ma, Jianjie; Dobrev, Dobromir; Zhang, Mingjie; Carnes, Cynthia A.; Vatta, Matteo; Rasband, Matthew N.; Hund, Thomas J.; Mohler, Peter J.

In: Circulation, Vol. 131, No. 8, 2015, p. 695-708.

Research output: Contribution to journalArticle

Smith, SA, Sturm, AC, Curran, J, Kline, CF, Little, SC, Bonilla, IM, Long, VP, Makara, M, Polina, I, Hughes, LD, Webb, TR, Wei, Z, Wright, P, Voigt, N, Bhakta, D, Spoonamore, KG, Zhang, C, Weiss, R, Binkley, PF, Janssen, PM, Kilic, A, Higgins, RS, Sun, M, Ma, J, Dobrev, D, Zhang, M, Carnes, CA, Vatta, M, Rasband, MN, Hund, TJ & Mohler, PJ 2015, 'Dysfunction in the βiI spectrin-dependent cytoskeleton underlies human arrhythmia', Circulation, vol. 131, no. 8, pp. 695-708. https://doi.org/10.1161/CIRCULATIONAHA.114.013708
Smith, Sakima A. ; Sturm, Amy C. ; Curran, Jerry ; Kline, Crystal F. ; Little, Sean C. ; Bonilla, Ingrid M. ; Long, Victor P. ; Makara, Michael ; Polina, Iuliia ; Hughes, Langston D. ; Webb, Tyler R. ; Wei, Zhiyi ; Wright, Patrick ; Voigt, Niels ; Bhakta, Deepak ; Spoonamore, Katherine G. ; Zhang, Chuansheng ; Weiss, Raul ; Binkley, Philip F. ; Janssen, Paul M. ; Kilic, Ahmet ; Higgins, Robert S. ; Sun, Mingzhai ; Ma, Jianjie ; Dobrev, Dobromir ; Zhang, Mingjie ; Carnes, Cynthia A. ; Vatta, Matteo ; Rasband, Matthew N. ; Hund, Thomas J. ; Mohler, Peter J. / Dysfunction in the βiI spectrin-dependent cytoskeleton underlies human arrhythmia. In: Circulation. 2015 ; Vol. 131, No. 8. pp. 695-708.
@article{20bb24902eec4ea7b3f13697068e5f7a,
title = "Dysfunction in the βiI spectrin-dependent cytoskeleton underlies human arrhythmia",
abstract = "Background: The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked to cardiac pathologies, including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction and cardiac electric activity is not well understood and often overlooked in the cardiac arrhythmia field. Methods and Results: Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that βII spectrin, an actin-associated molecule, is essential for the posttranslational targeting and localization of critical membrane proteins in heart. βII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/βII spectrin interaction, leading to severe human arrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electric and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, βII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes, including the Na/Ca exchanger, ryanodine receptor 2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in βII spectrin-deficient mice. Conclusions: Our findings identify βII spectrin as critical for normal myocyte electric activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.",
keywords = "Arrhythmias, Cardiac, Catecholaminergic polymorphic ventricular arrhythmia, Cytoskeleton, Ion channels, Protein transport, Ventricular tachycardia",
author = "Smith, {Sakima A.} and Sturm, {Amy C.} and Jerry Curran and Kline, {Crystal F.} and Little, {Sean C.} and Bonilla, {Ingrid M.} and Long, {Victor P.} and Michael Makara and Iuliia Polina and Hughes, {Langston D.} and Webb, {Tyler R.} and Zhiyi Wei and Patrick Wright and Niels Voigt and Deepak Bhakta and Spoonamore, {Katherine G.} and Chuansheng Zhang and Raul Weiss and Binkley, {Philip F.} and Janssen, {Paul M.} and Ahmet Kilic and Higgins, {Robert S.} and Mingzhai Sun and Jianjie Ma and Dobromir Dobrev and Mingjie Zhang and Carnes, {Cynthia A.} and Matteo Vatta and Rasband, {Matthew N.} and Hund, {Thomas J.} and Mohler, {Peter J.}",
year = "2015",
doi = "10.1161/CIRCULATIONAHA.114.013708",
language = "English",
volume = "131",
pages = "695--708",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "8",

}

TY - JOUR

T1 - Dysfunction in the βiI spectrin-dependent cytoskeleton underlies human arrhythmia

AU - Smith, Sakima A.

AU - Sturm, Amy C.

AU - Curran, Jerry

AU - Kline, Crystal F.

AU - Little, Sean C.

AU - Bonilla, Ingrid M.

AU - Long, Victor P.

AU - Makara, Michael

AU - Polina, Iuliia

AU - Hughes, Langston D.

AU - Webb, Tyler R.

AU - Wei, Zhiyi

AU - Wright, Patrick

AU - Voigt, Niels

AU - Bhakta, Deepak

AU - Spoonamore, Katherine G.

AU - Zhang, Chuansheng

AU - Weiss, Raul

AU - Binkley, Philip F.

AU - Janssen, Paul M.

AU - Kilic, Ahmet

AU - Higgins, Robert S.

AU - Sun, Mingzhai

AU - Ma, Jianjie

AU - Dobrev, Dobromir

AU - Zhang, Mingjie

AU - Carnes, Cynthia A.

AU - Vatta, Matteo

AU - Rasband, Matthew N.

AU - Hund, Thomas J.

AU - Mohler, Peter J.

PY - 2015

Y1 - 2015

N2 - Background: The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked to cardiac pathologies, including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction and cardiac electric activity is not well understood and often overlooked in the cardiac arrhythmia field. Methods and Results: Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that βII spectrin, an actin-associated molecule, is essential for the posttranslational targeting and localization of critical membrane proteins in heart. βII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/βII spectrin interaction, leading to severe human arrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electric and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, βII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes, including the Na/Ca exchanger, ryanodine receptor 2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in βII spectrin-deficient mice. Conclusions: Our findings identify βII spectrin as critical for normal myocyte electric activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.

AB - Background: The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked to cardiac pathologies, including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction and cardiac electric activity is not well understood and often overlooked in the cardiac arrhythmia field. Methods and Results: Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that βII spectrin, an actin-associated molecule, is essential for the posttranslational targeting and localization of critical membrane proteins in heart. βII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/βII spectrin interaction, leading to severe human arrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electric and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, βII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes, including the Na/Ca exchanger, ryanodine receptor 2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in βII spectrin-deficient mice. Conclusions: Our findings identify βII spectrin as critical for normal myocyte electric activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.

KW - Arrhythmias

KW - Cardiac

KW - Catecholaminergic polymorphic ventricular arrhythmia

KW - Cytoskeleton

KW - Ion channels

KW - Protein transport

KW - Ventricular tachycardia

UR - http://www.scopus.com/inward/record.url?scp=84923809412&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923809412&partnerID=8YFLogxK

U2 - 10.1161/CIRCULATIONAHA.114.013708

DO - 10.1161/CIRCULATIONAHA.114.013708

M3 - Article

VL - 131

SP - 695

EP - 708

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 8

ER -