Calmodulin Antagonists and Cell Energy Metabolism in Health and Disease

Abstract

zymes are known to be regulated by reversible bindCalmodulin is a multifunctional Ca-binding proing to the cytoskeleton (8, for reviews, see 1,9,10). tein that has been implicated in the regulation of They bind both to actin filaments and to tubulin/ numerous cellular events. The Ca-calmodulin commicrotubules (8–15). The binding of glycolytic enplex plays a central role in the control of cell energy zymes to cytoskeleton was demonstrated both in metabolism (for previous review, see 1). It has a dual vitro, using purified components (16–23), and in effect on cell ATP-producing systems; while an invivo, in whole tissues (7,24–26), as well as in differcrease in intracellular Ca at physiological range ent cultured cells (27–29). Glycolytic enzymes in of concentrations exerts (through Ca-calmodulin their cytoskeleton-bound form are known to be more complex) stimulatory effects on cell energy metaboactive than their soluble form (9). Their activation, lism, Ca at high pathological concentration causes as well as their proximity to each other when bound a decrease in cell ATP and cell damage, characteristo the cytoskeleton, provides a more efficient glycotic of various diseases. lytic flux. Cytoskeletal glycolysis provides local ATP The ATP-producing systems in the different cell in the vicinity of the cytoskeleton, which is known compartments, which are controlled by the Ca-calto interact dynamically with the plasma membrane modulin complex, are: (a) cytosolic glycolysis, (b) cyupon membrane-induced events. Binding of glycotoskeletal glycolysis, and (c) mitochondrial oxidative lytic enzymes to cytoskeleton also affects cell strucmetabolism, which is linked to mitochondrial-bound ture, as glycolytic enzymes were found to cross-link hexokinase (HK). actin-containing filaments into ordered supramolecThe chief allosteric regulator of cytosolic glycolysis ular structures (9). Many factors and conditions conin extrahepatic tissues is glucose 1,6-bisphosphate trol the binding of glycolytic enzymes to the cytoskel(Glc-1,6-P2) (for reviews, see Refs. 1–5). This cometon (1). pound acts as an intracellular signal which, through Hexokinase is the only glycolytic enzyme which its allosteric effects on the key enzymes of carbohydoes not bind to the cytoskeleton, but instead binds drate metabolism, regulates the different pathways reversibly to mitochondria (see reviews 30–32). HK of glucose metabolism under different conditions. binds to porin at the contact sites between the mito-