Phosphorylation and the control of calcium fluxes

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Abstract
Cell activation, e.g. stimulus-contraction or stimulus-secretion coupling, is brought about by a 100-fold increase in cytosolic free Ca 2+ concentration from 0.1 to 10 μm, upon release of Ca 2+ from intrareticular or extracellular stores along the concentration gradient. A return to steady state is achieved by either Na + -Ca2+Ca 2+ exchange or ATP-dependent Ca 2+ transport against the concentration gradient. Both processes, Ca 2+ influx and Ca 2+ efflux, are regulated by sophisticated covalent mechanisms. The positive inotropic effect of adrenalin is mediated by the cyclic-AMP-dependent phosphorylation of cardiac sarcolemmal proteins, among which calciductin is the major phosphate acceptor. Upon cyclic-AMP-dependent phosphorylation, the slow Ca 2+ channel is activated 3.5 times above its basal low- conductance state, and retains its characteristics, competition by divalent metals, inhibition by La 3+ and Ca 2+ entry blockers. The adrenalin-induced abbreviation of systole is also explained in terms of the dual phosphorylation of the cardiac sarcoplasmic reticulum calcium pump activator, phospholamban, by cyclic-AMP-dependent protein kinase on the one hand and Ca 2+ -calmodulin-dependent phospholamban kinase on the other. Calciductin and phospholamban are closely similar acidic proteolipids. A phospholamban-like protein is also found in platelet Ca 2+ -accumulating vesicles, where its cyclic-AMP-dependent phosphorylation doubles the rate of Ca 2+ efflux. These observations raise the possibility that calcium fluxes are regulated by phosphorylation of membrane-bound proteolipids. More generally, phosphorylation modulates K + , Na + and Ca 2+ fluxes through membranes, i.e. the general excitability properties of the cell.

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