The established ?sliding-filament theory? of muscle contraction, while it is adequate to explain actin-myosin force generation, does not suffice to account for changes in membrane lipid bilayer parallel to the sliding filament during sarcomere shortening. To reconcile this unexplained phenomenon, our group has spent the last decade trying to contend with this dilemma and have recently identified a mechanical amplifier, a non- conventional motor protein, prestin (Slc26a5) and its oligomer Slc26a6 in cardiac myocytes, serving as a muscle amplifier. Prestin is a member of the solute carrier (SLC) gene family. We hypothesize that prestin acts as a ?spring? to amplify actin-myosin force generation and accounts for the non-linear properties of muscle contraction. Specifically, we hypothesize that prestin is expressed in cardiac myocytes and serves as a non- conventional motor. Prestin is distinct in SLC26 family of proteins because of its molecular motor function in contrast to the anion transport functions of other members. We further hypothesize that Slc26a6 is required as an efficient transporter to create intracellular Cl- microdomain for the proper function of prestin. Using direct electrophysiological measurements, we demonstrate that prestin is indeed, a weak anion transporter compared with Slc26a6. To function effectively, prestin requires a strong anion exchanger for its optimal function. Thus, we hypothesize that prestin requires a ?team player?, Slc26a6, to form heteromeric proteins to perform distinct functions in cardiac myocytes. Collectively, our findings greatly challenge the current paradigm in the field and would not have been realized except for a close collaboration among seemingly disparate disciplines in neuroscience, cardiovascular, and biomedical engineering investigative units. 1

Public Health Relevance

Cardiovascular disease is the leading cause of mortality in United States and causes more deaths than all cancers combined. Prestin (Slc26a5) is a member of the Solute Carrier (SLC) gene family. Here, we propose to study the fundamental roles of prestin in the amplification of cardiac contraction. 1

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL137228-04
Application #
9902512
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Tjurmina, Olga A
Project Start
2017-04-01
Project End
2021-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Yeo, Khung-Keong; Armstrong, Ehrin J; López, Javier E et al. (2018) Aspirin and clopidogrel high on-treatment platelet reactivity and genetic predictors in peripheral arterial disease. Catheter Cardiovasc Interv 91:1308-1317
Zhang, Xiao-Dong; Coulibaly, Zana A; Chen, Wei Chun et al. (2018) Coupling of SK channels, L-type Ca2+ channels, and ryanodine receptors in cardiomyocytes. Sci Rep 8:4670
Gluck, Jessica M; Herren, Anthony W; Yechikov, Sergey et al. (2017) Biochemical and biomechanical properties of the pacemaking sinoatrial node extracellular matrix are distinct from contractile left ventricular matrix. PLoS One 12:e0185125
Frederich, Bert J; Timofeyev, Valeriy; Thai, Phung N et al. (2017) Electrotaxis of cardiac progenitor cells, cardiac fibroblasts, and induced pluripotent stem cell-derived cardiac progenitor cells requires serum and is directed via PI3'K pathways. Heart Rhythm 14:1685-1692
Fu, Qin; Hu, Yuting; Wang, Qingtong et al. (2017) High-fat diet induces protein kinase A and G-protein receptor kinase phosphorylation of ?2 -adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts. J Physiol 595:1973-1986
Sirish, Padmini; Ledford, Hannah A; Timofeyev, Valeriy et al. (2017) Action Potential Shortening and Impairment of Cardiac Function by Ablation of Slc26a6. Circ Arrhythm Electrophysiol 10:
López, Javier E; Sharma, Janhavi; Avila, Jorge et al. (2017) Novel large-particle FACS purification of adult ventricular myocytes reveals accumulation of myosin and actin disproportionate to cell size and proteome in normal post-weaning development. J Mol Cell Cardiol 111:114-122
Chiamvimonvat, Nipavan; Chen-Izu, Ye; Clancy, Colleen E et al. (2017) Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics. J Physiol 595:2229-2252
Kennedy, Matthew; Bers, Donald M; Chiamvimonvat, Nipavan et al. (2017) Dynamical effects of calcium-sensitive potassium currents on voltage and calcium alternans. J Physiol 595:2285-2297
Zhang, Zheng; Ledford, Hannah A; Park, Seojin et al. (2017) Distinct subcellular mechanisms for the enhancement of the surface membrane expression of SK2 channel by its interacting proteins, ?-actinin2 and filamin A. J Physiol 595:2271-2284

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