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Review Article Calmodulin and Its Roles in Skeletal Muscle Function

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Review Article Calmodulin and Its Roles in Skeletal Muscle Function 390 Review Article Calmodulin and its roles in skeletal Michael P. Walsh i'H D muscle function The purpose of this review is to describe the importance Calcium ions are recognized to be important intra- of calmodutin as a mediator of the effects of calcium ions cellular messengers involved in a host of physiolog- in living systems, particularly in the process of skeletal ical responses to nervous and hormonal stimuli, the muscle contraction. effects of Ca 2+ being mediated by specific Ca 2+- Calmodulin is a low molecular weight, acidic, calcium binding proteins) The second messenger con- binding protein which mediates the Ca2+ regulation of cept in relation to calcium ions is summarized in a wide range of physiological processes throughout Figure 1. eukaryotic organisms. At low free Ca2+ concentrations, An appropriate stimulus leads to an elevation of such as exist in resting muscle sarcoptasm, calmodulin cytosolic Ca 2+ concentration, this Ca 2+ coming exists in the Ca2+-free form in which state it does not from intraeellular stores or the extraeellular space. generally interact with a target protein_ Following an This cytosolic Ca 2+ then interacts with one or more appropriate stimulus, the free Ca2§ concentration rises calcium-binding proteins, depending on the tissue whereupon Ca2+ binds to calmodulin which undergoes a under consideration. These calciproteins form a conforn~ional change enabling it to interact with a target family of structurally homologous proteins, ex- protein(s). The overall result of this protein-protein amples of which are calmodulin (the subject of this interaction is aphysiological effect, e.g., Ca2+ binding to article), troponin C (which is a component of the calmodulin in smooth muscle allows it to interact with primary Ca z§ regulatory mechanism in striated and activate myosin light chain kinase which catalyzes muscles), mid parvalbmnins (the soluble relaxing the phasphorylation of myosin. This reaction results in factors of fast-twitch skeletal muscle). The resultant contraction of the smooth muscle. Recent studies have Ca2+-calcium binding protein complex is then implicated calmodulin in the Ca2+ control of three capable of interaction with one or more target eneymes in skeletal muscle: phosphorytose kinase, myosin proteins, again depending on the tissue under light chain kinase and a protein kinase of the sarco- consideration, to form a ternary complex of Ca 2+- plasmic reticulum. Various classes of drugs, btcluding calcium binding protein-target protein. The effect is certain local anaesthetics, have been shown to affect generally to convert the target protein (which is calmodulin-depeadent processes. It is likely ttmt the often an enzyme) from an inactive to an active state. effects of such drugs result from their interaction with The end-result of the targel protein activation is a catmodulin. physiological event which may be the immediate consequence of target protein activation or may Key words result from a series of intermediate reactions (usually MUSCLE, SKELETAL: calcium, ealmodulin, protein phosphorylations) triggered by the target glycogen metabolism, myosin phosphorylation, protein activation. sarcoplasmic reticulum. An obvious example to quote is contraction of skeletal muscle fibers in response to nervous stimula- tion which leads to an elevation of sarcoplasmic Fmm the Department of Medical Biochemistry, Faculty Ca 2§ concentration. These Ca 2§ ions interact with of Medicine, University of Calgary, Calgary, Alberta troponin C inducing a conformational change in the T2N 1N4. calcium binding protein which is transmitted to CAN ANAESTH SOC I 1983 t 30:4 / pp 390-398 Walsh: CALMODULIN 391 ways they are affected in disease conditions or Stimulus following administration of drugs or anaesthetics. t For this reason, it is hoped that this review will be t t useful and interesting to anaesthetists and other clinicians. t"ytosotic [Ca 2§ ] I" Ca 2+BP --~ Slructural aspects Calmodulin is a monomeric, globular protein of Ca2§ - Ca2+Bp molecular weight 417,000 daltons. It is a highly acidic protein (pI = 4.0-4.3) due to a high content (Inaetive) (-35 per cent) of aspartate and glutamate residues. Calmodulins lack tryptophan and, usually, cys- Ca2. - Ca2"BP-TP(active) teine. A high ratio of phenylalanine:tyrosine (com- I ! ! monly 8:2) gives rise to a characteristic UV absorp- ! tion spectrum which is atypical of common globular Physiological event proteins. Most calmodulins contain a single residue of the unusual amino acid, ~-N-trimethyllysine, Ca2+Bp = calcium binding protein which presumably arises from a post-translational TP = target protein. methylafion of a lysine residue. The amino-terminus of calmodulin is blocked by an N-acetyl group. FIGURE I Seeond messengerconcept. The amino acid sequences of nine calmodulins ranging from human brain to Tetrahymena pyri- neighbouring subunits of the troponin complex formis (a ciliated protozoan) have been completed causing a movement of tropomyosin into the aetin or almost completed, The primary structure of groove. This permits actin-myosin interaction and calmodulin is remarkably conserved throughout contraction of the muscle at the expense of ATP. 2 evolution, suggesting the importance of the entire Of the numerous calcium binding proteins studied molecule in the diverse functions of this calcium to date, calmodulin is the most widespread. It has binding protein. been purified to homogeneity from a wide range of Calmodulin is capable of binding 4 Ca 2§ ions specie~ and tissues from higher vertebrates (includ- ing man) through the invertebrates, higher plants, fungi, slime molds and unicellular organisms. 3 TABLE Diversity of ealmodulin function Calmodulin has been identified in every tissue and CMmodulin-dependent species of eukaryote examined; it has not, however, enzymes Physiological role been found in prokaryotes. In keeping with its wide- Cyclic nucleotide phospho- spread distribution, ealmodulin exhibits a great diesterase Cyclic nucleotide metabolism diversity of function as shown in the Table. Calmo- Adenylate cyclase dulin was originally identified as the Ca 2+- (Ca2+ - Mg2+) ATPases Ca 2+ transport dependent activator of bovine heart and brain cyclic Myosin light chain kirtase Smooth muscle contraction nucleotide phosphodiesterases by Cheung in the and non-muscle motility Phospho~lase kinase Glycogen metabolism U.S. 4 and Kalduchi in Japan) Soon afterwards it Other eaimodulin-dependent e.g. neurotransmitrer release was shown to activate brain adenylate cyclase, also kinases in a Ca2+-dependent manner. 6 Calmodulin has PhospholipaseA2 Platelet aggregation since been implicated in the regulation of a host of Dynein ATPase Ciliary and flagellar motility other key enzymes and physiological processes Other calmodulin-regulated processes (Table). Insulin secretion from pancreatic 13 cells Because of its widespread functional importance, Pancreatic enzyme secretion knowledge of ealmodulin and its roles in physio- Intestinal secretion logical processes is fundamental to eventual under- Platelet release reaction Platelet adhesion end plug formation standing of how living systems operate and in what 392 CANADIAN ANAESTHETISTS' SOCIETY /OURNAL per molecule with affinities in the range of -0.2- 3 txM. Thus in resting cells calmodulin will release 4Ca 2§ + CaM its Ca 2§ while in excited cells it will be saturated with Ca~§ . This provides the basis for calmodulin's roles in biological regulation. The 4 Ca2+ binding 1L sites in calmodulin and the individual Ca2+ coordi- Ca4~§ .CaM hating ligands have been predicted on the basis of the x-ray crystallographic sa-ucture of the homolo- gous calcium binding protein, carp parvalbumin, Ca~ 2+ "CAM* and the known amino acid sequence of calmodulin. The calmodulin molecule can be divided into four (inactive) approximately equal parts, each of which contains one Ca 2+ binding site. t Each of these four domains Ca,2+,CaM*,TE consists of an or-helical segment, followed by a Ca 2+ binding loop, followed by another ct helical Jt segment. Not surprisingly, the four domains exhibit Ca42 § C aM*.TE * (inactive) a considerable degree of sequence homology. *Denotes an activeconformation. Mechanism of action CaM = calmodulin. TE = target enzyme. An essential phase in the mechanism of activation of enzymes by ealmodulin is a conformational FIGURE 2 Mechanismof activationof target enzymesby change induced in calmodulin by I~inding of Ca z+ . ca]madulin. This results in exposure of a site(s) which can interact with the target enzyme. A considerable amount of evidence has been provided in support of this Ca2+-induced conformationat change. 3 Upon block the interaction of calmodulin with its target binding Ca:+, calmodulin becomes a more com- protein; calmodulin binds 2 moles of triltuoperazine/ pact, globular structure and a hydrophobic site mole with high affinity (Kn = 1.5 ~,M) only in the becomes exposed on the surface of the molecule. presence of Ca 2+. Levin and Weiss B made the This hydrophohic site is helieved to be involved in interesting observation that the phosphodiesterase the interaction of calmodulin with its target pro- inhibitory effects of a series of phenothiazines teins. Figure 2 illustrates the mechanism whereby correlated with their clinical effectiveness as anti- calmodulin activates most of its target enzymes. psychotic drugs. Furthermore, calmodulin-depen- dent pnosphodiesterase was inhibited by other Drug blndlng chemical classes of antipsychofics: bulyrophenones, The possibility that certain
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