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Mammalian skeletal muscle shows an enormous variability in its functional features such as rate of force production, resistance to fatigue, and energy metabolism, with a wide spectrum from slow aerobic to fast anaerobic physiology. In addition, skeletal muscle exhibits high plasticity that is based on the potential of the muscle fibers to undergo changes of their cytoarchitecture and composition of specific muscle protein isoforms. Adaptive changes of the muscle fibers occur in response to a variety of stimuli such as, e.g., growth and differentition factors, hormones, nerve signals, or exercise. Additionally, the muscle fibers are arranged in compartments that often function as largely independent muscular subunits. All muscle fibers use Ca(2+) as their main regulatory and signaling molecule. Therefore, contractile properties of muscle fibers are dependent on the variable expression of proteins involved in Ca(2+) signaling and handling. Molecular diversity of the main proteins in the Ca(2+) signaling apparatus (the calcium cycle) largely determines the contraction and relaxation properties of a muscle fiber. The Ca(2+) signaling apparatus includes 1) the ryanodine receptor that is the sarcoplasmic reticulum Ca(2+) release channel, 2) the troponin protein complex that mediates the Ca(2+) effect to the myofibrillar structures leading to contraction, 3) the Ca(2+) pump responsible for Ca(2+) reuptake into the sarcoplasmic reticulum, and 4) calsequestrin, the Ca(2+) storage protein in the sarcoplasmic reticulum. In addition, a multitude of Ca(2+)-binding proteins is present in muscle tissue including parvalbumin, calmodulin, S100 proteins, annexins, sorcin, myosin light chains, beta-actinin, calcineurin, and calpain. These Ca(2+)-binding proteins may either exert an important role in Ca(2+)-triggered muscle contraction under certain conditions or modulate other muscle activities such as protein metabolism, differentiation, and growth. Recently, several Ca(2+) signaling and handling molecules have been shown to be altered in muscle diseases. Functional alterations of Ca(2+) handling seem to be responsible for the pathophysiological conditions seen in dystrophinopathies, Brody's disease, and malignant hyperthermia. These also underline the importance of the affected molecules for correct muscle performance.

Calmodulin (CaM) is a ubiquitous Ca(2+) receptor protein mediating a large number of signaling processes in all eukaryotic cells. CaM plays a central role in regulating a myriad of cellular functions via interaction with multiple target proteins. This review focuses on the action of CaM and CaM-dependent signaling systems in the control of vertebrate cell proliferation, programmed cell death and autophagy. The significance of CaM and interconnected CaM-regulated systems for the physiology of cancer cells including tumor stem cells, and processes required for tumor progression such as growth, tumor-associated angiogenesis and metastasis are highlighted. Furthermore, the potential targeting of CaM-dependent signaling processes for therapeutic use is discussed.

The physiological role of the Ca2+-binding protein parvalbumin in skeletal muscle has been investigated by measuring the parvalbumin content by HPLC in a variety of mammalian muscles, including man, and comparing the results with the respective muscle relaxation properties and fiber type compositions. The parvalbumin concentrations were highest in the skeletal muscles of the smallest animal investigated (mouse, gastrocnemius: 4.9 g/kg), which has the highest relaxation speed, and lowest in the larger animals (horse, deep gluteal muscle: £0.001 g/kg) and man (vastus, triceps: £0.001 g/kg), which have much lower relaxation speeds. Analysis of three type-homogeneous muscles of the guinea pig revealed highest parvalbumin concentrations (0.25 g/kg) in sartorius (type IIB) and lowest concentrations (£0.007 g/kg) in soleus (type I), consistent with the different halfrelaxation times of fast and slow muscles. Denervation of the rat extensor digitorum longus, which increases the half-relaxation time from 9.4 to 19 msec, resulted in a 20% decrease of the parvalbumin content. Given this close correlation between parvalbumin content and relaxation speed in a variety of muscles and species, we suggest that parvalbumin is involved directly in the relaxation process in fast muscles.Two opposing hypotheses coexist about the role of the Ca2+-binding protein parvalbumin in the contraction-relaxation cycle of skeletal muscle. On the basis of kinetic experiments it was proposed that muscle parvalbumin is a relaxing factor capable of removing Ca2' ions from the myofibrillar Ca +-binding subunit of troponin, troponin C, and then passing the Ca2' ions to the sarcoplasmic reticulum (1)(2)(3)(4). On the other hand, it was concluded that parvalbumin cannot be involved directly in the rapid decay of tension in a single twitch of muscle essentially because of the slow Ca2' "on" rate (in relaxed muscle fibers Mg2e is bound to parvalbumin and must be removed first) and because of the slow Ca2+ "off" rate (resulting from the high affinity of these sites for Ca2+) (5-7). Thus, despite a similar experimental approach there is disagreement about the in vivo Ca2+-binding properties and the functional role ofparvalbumin.We chose to approach this problem from a different point of view by comparing the parvalbumin concentrations, determined by HPLC and two-dimensional (2-D) gel electrophoresis, with the contraction and relaxation properties of a variety of muscles of several mammalian species, including man.If parvalbumin is involved in the relaxation process of muscles, its distribution and concentration must fulfil the following criteria:(i) Within any single species of animal more parvalbumin should be present in muscles known to have fast relaxation times than in muscles that relax slowly.(ii) Similarly, on a much more general level, within each species, the parvalbumin content of individual muscles should be related to their fiber type composition, with more parvalbumin present in muscles with a high proportion of fast-twitch (type II)...

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Cytosolic and nuclear Ca2؉ have been shown to differentially regulate transcription. However, the impact of spatially distinct Ca 2؉ signals on mitogen-activated protein kinase-mediated gene expression remains unknown. Here we investigated the role of nuclear and cytosolic Ca 2؉ signals in epidermal growth factor (EGF)-induced transactivation of the ternary complex factor Elk-1 using a GAL4-Elk-1 construct. EGF increased Ca

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