title: Cardiac specific expression of threonine 5 to alanine mutant sarcolipin results in structural remodeling and diastolic dysfunction.
abstract: The functional importance of threonine 5 (T5) in modulating the activity of sarcolipin (SLN), a key regulator of sarco/endoplasmic reticulum (SR) Ca2+ ATPase (SERCA) pump was studied using a transgenic mouse model with cardiac specific expression of threonine 5 to alanine mutant SLN (SLNT5A). In these transgenic mice, the SLNT5A protein replaces the endogenous SLN in atria, while maintaining the total SLN content. The cardiac specific expression of SLNT5A results in severe cardiac structural remodeling accompanied by bi-atrial enlargement. Biochemical analyses reveal a selective downregulation of SR Ca2+ handling proteins and a reduced SR Ca2+ uptake both in atria and in the ventricles. Optical mapping analysis shows slower action potential propagation in the transgenic mice atria. Doppler echocardiography and hemodynamic measurements demonstrate a reduced atrial contractility and an impaired diastolic function. Together, these findings suggest that threonine 5 plays an important role in modulating SLN function in the heart. Furthermore, our studies suggest that alteration in SLN function can cause abnormal Ca2+ handling and subsequent cardiac remodeling and dysfunction.
authors: Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
authors: Mayilvahanan
authors: M
authors: Shanmugam
authors: Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
authors: Dan
authors: D
authors: Li
authors: Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
authors: Shumin
authors: S
authors: Gao
authors: Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
authors: Nadezhda
authors: N
authors: Fefelova
authors: Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
authors: Vikas
authors: V
authors: Shah
authors: Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
authors: Antanina
authors: A
authors: Voit
authors: Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
authors: Ronald
authors: R
authors: Pachon
authors: Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
authors: Ghassan
authors: G
authors: Yehia
authors: Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
authors: Lai-Hua
authors: LH
authors: Xie
authors: Department of Cell Biology and Molecular Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, United States of America.
authors: Gopal J
authors: GJ
authors: Babu
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003971:Diastole / Q000235:genetics; D015870:Gene Expression; D006325:Heart Atria / Q000378:metabolism; D006439:Hemodynamics; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D009928:Organ Specificity / Q000235:genetics; D011510:Proteolipids / Q000235:genetics* / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013912:Threonine / Q000235:genetics* / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000235:genetics*; D020257:Ventricular Remodeling / Q000235:genetics*
chemical_list: D009124:Muscle Proteins; D011510:Proteolipids; C077258:sarcolipin; D013912:Threonine; D002118:Calcium