## Abstract

Cell activation, e.g. stimulus-contraction or stimulus-secretion coupling, is brought about by a 100-fold increase in cytosolic free Ca<latex>$^{2+}$</latex> concentration from 0.1 to 10 <latex>$\mu M$</latex>, upon release of Ca<latex>$^{2+}$</latex> from intrareticular or extracellular stores along the concentration gradient. A return to steady state is achieved by either Na<latex>$^+$</latex>-Ca<latex>$^{2+}$</latex> exchange or ATP-dependent Ca<latex>$^{2+}$</latex> transport against the concentration gradient. Both processes, Ca<latex>$^{2+}$</latex> influx and Ca<latex>$^{2+}$</latex> 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<latex>$^{2+}$</latex> channel is activated 3.5 times above its basal low- conductance state, and retains its characteristics, competition by divalent metals, inhibition by La<latex>$^{3+}$</latex> and Ca<latex>$^{2+}$</latex> 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<latex>$^{2+}$</latex>-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<latex>$^{2+}$</latex>-accumulating vesicles, where its cyclic-AMP-dependent phosphorylation doubles the rate of Ca<latex>$^{2+}$</latex> efflux. These observations raise the possibility that calcium fluxes are regulated by phosphorylation of membrane-bound proteolipids. More generally, phosphorylation modulates K<latex>$^+$</latex>, Na<latex>$^+$</latex> and Ca<latex>$^{2+}$</latex> fluxes through membranes, i.e. the general excitability properties of the cell.