Contributions of troponin I and troponin C to the acidic pH-induced depression of contractile Ca2+ sensitivity in cardiotrabeculae.
Acid pH diminishes the Ca2+ sensitivity for force generation in both cardiac and skeletal muscles, but the mechanisms for these remain undetermined. In permeabilized (skinned) single myofibers of fast-twitch skeletal muscle of the rat, we find that pCa50 of the pCa-force relationship was 5.73 in pH 7 and 5.02 in pH 6.2 (delta pKskeletal = pCa50 in pH 7-pCa50 in pH 6.2 = 0.71 pCa unit); on the other hand, in skinned cardiotrabeculae, the hpCa50 was 5.79 in pH 7 decreasing to 4.14 in pH 6.2 (delta pKcardiac = 1.65 pCa units). We have used this large differential between cardiac/skeletal delta pKs to probe the mechanisms of the pH effects. Since troponin C (TnC) and troponin I (TnI) each have a central role in the Ca2+ switch, we exchanged these proteins in cardiac muscle with their skeletal counterparts and reinvestigated the pH effects. Firstly, with fast-twitch skeletal muscle (sTnC) substituting for 80% of the endogenous cardiac TnC (cTnC), the cardiac pH effect was decreased marginally (modified delta pK = 1.39 pCa units). This TnC-mediated change was further probed with two distinct cardiac-skeletal TnC chimeras, c1/s and CBc1/s (the Ca(2+)-binding c1/s), in which a majority of the N-terminal 41 amino acid residues was made cardiac and the rest skeletal [Gulati, J., & Rao, V. G. (1994) Biochemistry 33, 9052-9056]. The phenotype shift following sTnC/cTnC exchange in the trabeculae was blocked when c1/s was used in lieu of sTnC; on the other hand, interestingly, CBc1/s exactly mimicked sTnC.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461.
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D000138:Acidosis / Q000503:physiopathology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D014336:Troponin / Q000378:metabolism*; D019209:Troponin C; D019210:Troponin I; D020107:Troponin T; D014638:Vanadates / Q000494:pharmacology
D014336:Troponin; D019209:Troponin C; D019210:Troponin I; D020107:Troponin T; D014638:Vanadates; D002118:Calcium