An internal domain of β-tropomyosin increases myofilament Ca2+ sensitivity
| Autor: | R. John Solaro, Rafeeq P.H. Ahmed, Ganapathy Jagatheesan, Tao Wang, Muhammad Ashraf, Natalia Petrashevskaya, David F. Wieczorek, Greg P. Boivin, Yigang Wang, Grace M. Arteaga, John N. Lorenz, Stephen B. Liggett, Emily M. Schulz, Arnold Schwartz, Sudarsan Rajan |
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| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Gene isoform
Sarcomeres Myofilament medicine.medical_specialty Protein Denaturation Cardiotonic Agents Physiology chemistry.chemical_element Tropomyosin Biology Calcium In Vitro Techniques Mice Physiology (medical) Internal medicine medicine Animals Myelin Sheath Circular Dichroism Isoproterenol Articles Adrenergic beta-Agonists Myocardial Contraction Recombinant Proteins Blot Actin Cytoskeleton Blotting Southern Endocrinology chemistry Amino Acid Substitution Echocardiography Circulatory system Mutation Biophysics RNA medicine.symptom Isoelectric Focusing Cardiology and Cardiovascular Medicine Ca2 sensitivity Muscle contraction |
| Popis: | Tropomyosin (TM) is involved in Ca2+-mediated muscle contraction and relaxation in the heart. Striated muscle α-TM is the major isoform expressed in the heart. The expression of striated muscle β-TM in the murine myocardium results in a decreased rate of relaxation and increased myofilament Ca2+sensitivity. Replacing the carboxyl terminus (amino acids 258–284) of α-TM with β-TM (a troponin T-binding region) results in decreased rates of contraction and relaxation in the heart and decreased myofilament Ca2+sensitivity. We hypothesized that the putative internal troponin T-binding domain (amino acids 175–190) of β-TM may be responsible for the increased myofilament Ca2+sensitivity observed when the entire β-TM is expressed in the heart. To test this hypothesis, we generated transgenic mice that expressed chimeric TM containing β-TM amino acids 175–190 in the backbone of α-TM (amino acids 1–174 and 191–284). These mice expressed 16–57% chimeric TM and did not develop cardiac hypertrophy or any other morphological changes. Physiological analysis showed that these hearts exhibited decreased rates of contraction and relaxation and a positive response to isoproterenol. Skinned fiber bundle analyses showed a significant increase in myofilament Ca2+sensitivity. Biophysical experiments demonstrated that the exchanged amino acids did not influence the flexibility of the TM. This is the first study to demonstrate that a specific domain within TM can increase the Ca2+sensitivity of the thin filament and affect sarcomeric performance. Furthermore, these results enhance the understanding of why TM mutations associated with familial hypertrophic cardiomyopathy demonstrate increased myofilament sensitivity to Ca2+. |
| Databáze: | OpenAIRE |
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