Advertisement

Canadian Anaesthetists’ Society Journal

, Volume 30, Issue 4, pp 390–398 | Cite as

Review Article Calmodulin and its roles in skeletal muscle function

  • Midiael P. Walsh
Article

Abstract

The purpose of this review is to describe the importance of calmodulin as a mediator of the effects of calcium ions in living systems, particularly in the process of skeletal muscle contraction.

Calmodulin is alow molecular weight, acidic, calcium binding protein which mediates the Co2+ regulation of a wide range of physiological processes throughout eukaryotic organisms. At low free Co2+ concentrations, such as exist in resting muscle sarcoplasm, calmodulin exists in the Ca2+ -free form in which stale it does noi generally interact with a target protein. Following an appropriate stimulus, the free Co2+ concentration rises whereupon Co2+ binds to calmodulin which undergoes a canformational change enabling it to interact with a target protein(s). The overall result of this protein-protein interaction isaphysiologicaleffect, e.g., Ca2+ binding to calmodulin in smooth muscle allows it to interact with and activate myosin light chain kinase which catalyzes the phosphorylation of myosin. This reaction results in contraction of the smooth muscle. Recent studies have implicated calmodulin in the Ca2+ control of three enzymes in skeletal muscle: phosphorylase kinase, myosin light chain kinase and a protein kinase of the sarcoplasmic reticulum. Various classes of drugs, including certain local anaesthetics, have been shown to affect calmodulin-dependent processes. It is likely that the effects of such drugs result from their interaction with calmodulin.

Key words

muscle skeletal calcium calmodulin glycogen metabolism myosin phosphorylation sarcoplasmic reticulum 

Résumé

Cette revue vise à décrire F importance de la calmoduline comme médiateur des effets des ions calciques dans les systèmes biologiques, surtout dans le processus de la contraction musculaire squelettique.

La caimoduline est une protéine acide de faible poids moléculaire, liant le calcium, qui agit comme médiateur dans la régulation du calcium pour une variété de processus physiologiques d’organismes eukariotiques. A une basse concentration de calcium libre, celle existant dans le sarcoplasme du muscle au repos, la calmoduline est sous forme libre, non liée au calcium, forme dans laquelle elle ne peut généralement pas réagir avec une protéine cible.

Après un stimulus approprié, la concentration du calcium libre s’élève jusqu’à ce que celui-ci se lie à la calmoduline qui subit alors un changement de configuration la rendant apte à réagir avec une ou des protêine(s) cible(s). Le résultat final de cette interaction protéine-protéine est un effet physiologique: par exemple, le calcium libre se liant à la calmoduline du muscle lisse lui permet de réagir avec la myosine kinase à chaîne légère qui catalyse ta phosphorisation de la myosine. Cette réaction amène la contraction du muscle lisse. Des études récentes ont impliqué la calmoduline dans le contrôle calcique de trois enzymes du muscle squelettique: la phosphorylase-kinase, la myosine-kinase à chaîne légère et la protéine-kinase du reticulum sarcoplasmi-que. On a démontré que des médicaments dont certains anesthésiques locaux, affectent les processus dépendant de la calmoduline probablement par une inter-réaction avec celle-ci.

References

  1. 1.
    Kretsinger RH. Structure and evolution of calcium-modulated proteins. CRC Crit Rev Biochem 1980; 8:119–74.PubMedCrossRefGoogle Scholar
  2. 2.
    Weber A, Murray JM, Molecular control mechanisms in muscular contraction. Physiol Rev 1973; 53:612–73.PubMedGoogle Scholar
  3. 3.
    Walsh MP, Hartshorne DJ. The Biochemistry of Smooth Muscle (N.L. Stephens, ed.) CRC Press, in press.Google Scholar
  4. 4.
    Cheung WY. Cyclic 3′,5′-nucleotide phosphodiesterase. Demonstration of an activator. Biochem Biophys Res Commun dy1970; 533-8.Google Scholar
  5. 5.
    Kakiuchi S, Yamazaki R, Nakajima H. Properties of a heat-stable phosphodiesterase activating factor isolated from brain extracts. Studies on cyclic 3′,5′-nucleotide phosphodiesterase II. Proc Jap Acad 1970; 46:587–92.Google Scholar
  6. 6.
    Brostrom CO, Huang YC, Breckenridge B. McL, Wolff DJ. Identification of a calcium-binding protein as a calcium-dependent regulator of brain adenylate cyclase. Proc Natl Acad Sci (USA) 1975; 72:64–8.CrossRefGoogle Scholar
  7. 7.
    Uzunov P, Weiss B. Effects of phenothiazine tranquilizers on the cyclic 3’,5’-adenosine monophosphate system of rat brain. Neuropharmacology 1971; 10:697–708.PubMedCrossRefGoogle Scholar
  8. 8.
    Levin RM, Weiss B. Mechanism by which psychotropic drugs inhibit adenosine cyclic 3′,5′-monophosphate phosphodiesterase in brain. Mol Pharmacol 1976; 12:581–98.PubMedGoogle Scholar
  9. 9.
    Cohen P. The subunit structure of rabbit-skeletal-muscle phosphorylase kinase, and the molecular basis of its activation reactions. Eur J Biochem 1973; 34:1–14.PubMedCrossRefGoogle Scholar
  10. 10.
    Cohen P, Burchell A, Foulkes JG, Cohen PTW, Vanaman TC, Nairn AC. Identification of the calcium-dependent modulator protein as the fourth sub-unit of rabbit skeletal muscle phosphorylase kinase. FEBS Utters 1978; 92:287–93.CrossRefGoogle Scholar
  11. 11.
    Embi N, Rylatt DB, Cohen P. Glycogen synthase kinase-2 and phosphorylase kinase are the same enzyme. Eur J Biochem 1979; 100:339–47.PubMedCrossRefGoogle Scholar
  12. 12.
    Huxley AF. Muscle structure and theories of contraction. Prog Biophys MolBio 1957:257-318.Google Scholar
  13. 13.
    Huxley HE, Hanson J. Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation. Nature 1954; 173:973–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Perrie WT, Smillie IB, Perry SV. A phosphoryl- ated light-chain component of myosin from skeletal muscle. Biochem J 1973; 135:151–64.PubMedGoogle Scholar
  15. 15.
    Walsh MP. Calmodulin-dependent myosin light chain kinases. Cell Calcium 1981; 2:333–52.PubMedCrossRefGoogle Scholar
  16. 16.
    Walsh MP, Hartshorne DJ. Actomyosin of smooth muscle in Calcium and Cell Function (W.Y. Cheung, ed.) 1982; 3:223–69.Google Scholar
  17. 17.
    Manning DR, Stull JT. Myosin light chain phos-phorylation and phosphorylase a activity in rat extensor digitorum longus muscle. Biochem Biophys Res Commun 1979; 90:164–70.PubMedCrossRefGoogle Scholar
  18. 18.
    Klug CA, Botlerman DR, Stull JT. The effect of low frequency stimulation on myosin tight chain phos-phorylation in skeletal muscle. J Biol Chem 1982; 257:4688–90.PubMedGoogle Scholar
  19. 19.
    Crow MT, Kushmerick MJ, Myosin light chain phosphorylation is associated with a decrease in the energy cost for contraction in fast twitch mouse muscle. J Biol Chem 1982; 257:2121–4.PubMedGoogle Scholar
  20. 20.
    Cooke R, Franks K, Stull JT. Myosin phosphorylation regulates the ATPase activity of permeable skeletal muscle fibers. FEBS Utters 1982; 144:33–7.CrossRefGoogle Scholar
  21. 21.
    Chiesi M, Carafoli E. The regulation of Ca3+ transport by fast skeletal muscle sarcoplasmic reticulum. Role of calmodulin and of the 53,000-dalton glycoprotein. J Biol Chem 1982; 257:984–91.PubMedGoogle Scholar
  22. 22.
    Campbell KP, MacLennan OH. A calmodulin-dependent protein kinase system from skeletal muscle sarcoplasmic reticulum. Phosphorylation of a 60,000-dalton protein. J Biol Chem 1982; 257:1238–46.PubMedGoogle Scholar
  23. 23.
    Tada M, Kirchberger MA, Kalz AM. Phosphorylation of a 22,000-dalton component of the cardiac sarcoplasmic reticulum by adenosine 3′:5′-mono-phosphate-dependent protein kinase. J Biol Chem 1975; 250:2640–7.PubMedGoogle Scholar
  24. 24.
    LePeuih CJ, Haiech J, Démaille JG. Concerted regulation of cardiac sarcoplasmic reticulum calcium transport by cyclic adenosine monophosphate dependent and calcium-calmodulin-dependent phos-phorylations. Biochemistry 1979; 18:5150–7.CrossRefGoogle Scholar
  25. 25.
    Kirchberger MA, Antonetz T. Calmodulin-mediated regulation of calcium transport and (Ca2+ + Mg2+)-activated ATPase activity in isolated cardiac sarcoplasmic reticulum. J Biol Chem 1982; 257:5685–91.PubMedGoogle Scholar
  26. 26.
    Grand RJA, Perry SV. Calmodulin-binding proteins from brain and other tissues. Biochem J 1979; 183:285–95.PubMedGoogle Scholar

Copyright information

© Canadian Anesthesiologists 1983

Authors and Affiliations

  • Midiael P. Walsh
    • 1
  1. 1.Department of Medical BiochemistryUniversity of CalgaryCalgary

Personalised recommendations