| First Author | Gaffin RD | Year | 2004 |
| Journal | J Physiol | Volume | 556 |
| Issue | Pt 2 | Pages | 531-43 |
| PubMed ID | 14766940 | Mgi Jnum | J:133808 |
| Mgi Id | MGI:3784309 | Doi | 10.1113/jphysiol.2003.058487 |
| Citation | Gaffin RD, et al. (2004) Charged residue changes in the carboxy-terminus of alpha-tropomyosin alter mouse cardiac muscle contractility. J Physiol 556(Pt 2):531-43 |
| abstractText | Striated muscle tropomyosin (TM) is an essential thin filament protein that is sterically and allosterically involved in calcium-mediated cardiac contraction. We have previously shown that overexpressing the beta-TM isoform in mouse hearts leads to physiological changes in myocardial relaxation and Ca(2+) handling of myofilaments. Two important charge differences in beta-TM compared to alpha-TM are the exchange of serine and histidine at positions 229 and 276 with glutamic acid and asparagine, respectively, imparting a more negative charge to beta-TM relative to alpha-TM. Our hypothesis is that the net charge at specific sites on TM might be a major determinant of its role in modulating cardiac muscle performance and in regulating Ca(2+) sensitivity of the myofilaments. To address this, we generated transgenic (TG) double mutation mouse lines (alpha-TM DM) expressing mutated alpha-TM at the two residues that differ between alpha- and beta-TM (Ser229Glu + His276Asn). Molecular analyses show 60-88% of the native TM is replaced with alpha-TM DM in the different TG lines. Work-performing heart analyses show that alpha-TM DM mouse hearts exhibit decreased rates of pressure development and relaxation (+dP/dt and -dP/dt). Skinned myofibre preparations from the TG hearts indicate a decrease in calcium sensitivity of steady state force. Protein modelling studies show that these two charge alterations in alpha-TM cause a change in the surface charges of the molecule. Our results provide the first evidence that charge changes at the carboxy-terminal of alpha-TM alter the functional characteristics of the heart at both the whole organ and myofilament levels. |
