Harpers

HORMONE ACTION & SIGNAL TRANSDUCTION / 463laxation and are potent vasodilators. These agents increasecGMP by activating the soluble form of guanylylcyclase, and inhibitors of cGMP phosphodiesterase (thedrug sildenafil [Viagra], for example) enhance and prolongthese responses. The increased cGMP activatescGMP-dependent protein kinase (PKG), which in turnphosphorylates a number of smooth muscle proteins.Presumably, this is involved in relaxation of smoothmuscle and vasodilation.Several Hormones Act ThroughCalcium or PhosphatidylinositolsIonized calcium is an important regulator of a variety ofcellular processes, including muscle contraction, stimulus-secretioncoupling, the blood clotting cascade, enzymeactivity, and membrane excitability. It is also anintracellular messenger of hormone action.A. CALCIUM METABOLISMThe extracellular calcium (Ca 2+ ) concentration is about5 mmol/L and is very rigidly controlled. Although substantialamounts of calcium are associated with intracellularorganelles such as mitochondria and the endoplasmicreticulum, the intracellular concentration of free orionized calcium (Ca 2+ ) is very low: 0.05–10 µmol/L. Inspite of this large concentration gradient and a favorabletransmembrane electrical gradient, Ca 2+ is restrainedfrom entering the cell. A considerable amountof energy is expended to ensure that the intracellularCa 2+ is controlled, as a prolonged elevation of Ca 2+ inthe cell is very toxic. A Na + /Ca 2+ exchange mechanismthat has a high capacity but low affinity pumps Ca 2+out of cells. There also is a Ca 2+ /proton ATPase-dependentpump that extrudes Ca 2+ in exchange for H + . Thishas a high affinity for Ca 2+ but a low capacity and isprobably responsible for fine-tuning cytosolic Ca 2+ .Furthermore, Ca 2+ ATPases pump Ca 2+ from the cytosolto the lumen of the endoplasmic reticulum. Thereare three ways of changing cytosolic Ca 2+ : (1) Certainhormones (class II.C, Table 42–3) by binding to receptorsthat are themselves Ca 2+ channels, enhance membranepermeability to Ca 2+ and thereby increase Ca 2+influx. (2) Hormones also indirectly promote Ca 2+ influxby modulating the membrane potential at theplasma membrane. Membrane depolarization opensvoltage-gated Ca 2+ channels and allows for Ca 2+ influx.(3) Ca 2+ can be mobilized from the endoplasmic reticulum,and possibly from mitochondrial pools.An important observation linking Ca 2+ to hormoneaction involved the definition of the intracellular targetsof Ca 2+ action. The discovery of a Ca 2+ -dependent regulatorof phosphodiesterase activity provided the basisfor a broad understanding of how Ca 2+ and cAMP interactwithin cells.B. CALMODULINThe calcium-dependent regulatory protein is calmodulin,a 17-kDa protein that is homologous to the muscleprotein troponin C in structure and function.Calmodulin has four Ca 2+ binding sites, and full occupancyof these sites leads to a marked conformationalchange, which allows calmodulin to activate enzymesand ion channels. The interaction of Ca 2+ with calmodulin(with the resultant change of activity of the latter)is conceptually similar to the binding of cAMP to PKAand the subsequent activation of this molecule.Calmodulin can be one of numerous subunits of complexproteins and is particularly involved in regulatingvarious kinases and enzymes of cyclic nucleotide generationand degradation. A partial list of the enzymes regulateddirectly or indirectly by Ca 2+ , probably throughcalmodulin, is presented in Table 43–4.In addition to its effects on enzymes and ion transport,Ca 2+ /calmodulin regulates the activity of manystructural elements in cells. These include the actinmyosincomplex of smooth muscle, which is under β-adrenergic control, and various microfilament-mediatedprocesses in noncontractile cells, including cellmotility, cell conformation changes, mitosis, granule release,and endocytosis.C. CALCIUM IS AMEDIATOR OF HORMONE ACTIONA role for Ca 2+ in hormone action is suggested by theobservations that the effect of many hormones is (1)blunted by Ca 2+ -free media or when intracellular calciumis depleted; (2) can be mimicked by agents thatincrease cytosolic Ca 2+ , such as the Ca 2+ ionophoreA23187; and (3) influences cellular calcium flux. Theregulation of glycogen metabolism in liver by vasopressinand α-adrenergic catecholamines provides agood example. This is shown schematically in Figures18–6 and 18–7.Table 43–4. Enzymes and proteins regulated bycalcium or calmodulin.Adenylyl cyclaseCa 2+ -dependent protein kinasesCa 2+ -Mg 2+ ATPaseCa 2+ -phospholipid-dependent protein kinaseCyclic nucleotide phosphodiesteraseSome cytoskeletal proteinsSome ion channels (eg, L-type calcium channels)Nitric oxide synthasePhosphorylase kinasePhosphoprotein phosphatase 2BSome receptors (eg, NMDA-type glutamate receptor)