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Titolo:
The effect of Mg2+ on cardiac muscle function: is CaATP the substrate for priming myofibril cross-bridge formation and Ca2+ reuptake by the sarcoplasmic reticulum?
Autore:
Smith, GA; Vandenberg, JI; Freestone, NS; Dixon, HBF;
Indirizzi:
Univ Cambridge, Dept Biochem, Cardiovasc Sci Sect, Sect Cardiovasc Biol, Cambridge CB2 1QW, England Univ Cambridge Cambridge England CB2 1QW iol, Cambridge CB2 1QW, England St Thomas Hosp, Guys Kings & St Thomas Sch Biomed Sci, Rayne Inst, London SE1 7EH, England St Thomas Hosp London England SE1 7EH ayne Inst, London SE1 7EH, England
Titolo Testata:
BIOCHEMICAL JOURNAL
, volume: 354, anno: 2001,
parte:, 3
pagine: 539 - 551
SICI:
0264-6021(20010315)354:<539:TEOMOC>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
INTRACELLULAR FREE MG2+; BOUND CREATINE-KINASE; SKELETAL-MUSCLE; CONTRACTILE FAILURE; CALCIUM-BINDING; ATP HYDROLYSIS; TROPONIN-C; ADENOSINE-TRIPHOSPHATASE; ELECTRON-MICROSCOPY; MYOCARDIAL-ISCHEMIA;
Keywords:
acetoxymethyl citrate; myofibrillar ATPase; phosphocreatine; sarcoplasmic reticulum; ATPase;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
77
Recensione:
Indirizzi per estratti:
Indirizzo: Smith, GA Univ Cambridge, Dept Biochem, Cardiovasc Sci Sect, Sect Cardiovasc Biol, Bldg O,Downing Site, Cambridge CB2 1QW, England Univ Cambridge Bldg O,Downing Site Cambridge England CB2 1QW nd
Citazione:
G.A. Smith et al., "The effect of Mg2+ on cardiac muscle function: is CaATP the substrate for priming myofibril cross-bridge formation and Ca2+ reuptake by the sarcoplasmic reticulum?", BIOCHEM J, 354, 2001, pp. 539-551

Abstract

These require two troponin Ca2+-binding sites, one for each myosin head, to act as a single unit in initial cross-bridge formation. This defines the first, or activating, ATPase reaction, as distinct from the further activity of the enzyme that continues when a cross-bridge to actin is already established. The pairing of myosin heads to act as one unit suggests a possiblealternating mechanism for muscle action. A large positive inotropic (contraction-intensifying) effect of loading the Mg2+ chelator citrate, via its acetoxymethyl ester, into the heart has confirmed the competitive inhibitionof the Ca2+ activation by Mg2+, previously seen in vitro. In the absence of a recognized second Ca2+-binding site on the myofibril, with appropriate binding propel ties, the bound ATP is proposed as the second activating Ca2-binding site. As ATP, free or bound to protein, call bind either Mg2+ or Ca2+, this leads to competitive inhibition by Mg2+. Published physico-chemical studies on skeletal muscle have shown that CaATP is potentially a more effective substrate than MgATP for cross-bridge formation. The above considerations allow calculation of the observed variation of fractional activation by Ca2+ as a function of [Mg2+] and in turn reveal simple Michaelis-Menten kinetics for the activation of the ATPase by sub-millimolar [Mg2+]. Furthermore the ability of bound ATP to bind either cation, and the much betterpromotion of cross-bridge formation by CaATP binding, give rise to the observed variation of the Hill coefficient for Ca2+ activation with altered [Mg2+]. The inclusion of CaADP within the initiating cross-bridge and replacement by MgADP during the second cycle is consistent with the observed fall in the rate of the myofibril ATPase that occurs after two phosphates are released. The similarity of the kinetics of the cardiac sarcoplasmic reticulum ATPase to those of the myofibril, in particular the positive co-operativity of both Mg2+ inhibition and Ca2+ activation, leads to the conclusion that this ATPase also has an initiation step that utilizes CaATP. The first-order activation by sub-millimolar [Mg2+], similar to that of the myofibril, may be explained by Mg2+ involvement in the phosphate-release step of the ATPase. The inhibition of both the myofibril and sarcoplasmic reticulum Ca2+-transporting ATPases by Mg2+ offers an explanation for the specific requirement for phosphocreatine (PCr) for full activity of both enzymes in situ and its effect on their apparent affinities for ATP. This explanation is based on the slow diffusion of Mg2+ within the myofibril and on the contrast of PCr with both ATP and phosphoenolpyruvate, in that PCr does not bind Mg2under physiological conditions, whereas both the other two bind it more tightly than the products of their hydrolysis do. The switch to supply of energy by diffusion of MgATP into the myofibril when depletion of PCr raises [ATP]/[PCr] greatly, e.g. during anoxia, results in a local [Mg2+] increase,which inhibits the ATPase. It is possible that mechanisms similar to thosedescribed above occur in skeletal muscle but the Ca2+ co-operativity involved would be masked by the presence of two Ca2+-binding sites on each troponin.

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Documento generato il 25/11/20 alle ore 07:30:31