Receptor-enzyme system

Another receptor-enzyme system was elucidated, which forms a guanylate cyclase. This enzyme converts GTP to cGMP upon receptor binding on the outer surface. The resulting cGMP activates either a protein kinase or a phosphodiesterase. 

It appears that insulin and certain growth factors may exert their effects by acting through this type of tyrosine kinase receptor-enzyme system.21,44 Insulin, for example, binds to the extracellular component of a protein located on skeletal muscle cells, thereby initiating activation of this protein s enzymatic activity on the inner surface of the cell membrane. This change in enzyme function causes further changes in cell activity, which ultimately result in increased glucose uptake in the muscle cell. The function of insulin receptors and their role in the cause and treatment of diabetes mellitus are discussed in more detail in Chapter 32. 

Cortisol-Cortisone Conversion. Under normal conditions, this equilibrium slightly favors the oxidized compound. Similarly, the conversion of corticosterone to 11-deoxycorticosterone is also mediated by the liP-hydroxysteroid dehydrogenase enzyme system and requites NAD(P) /NAD(P)H. This conversion is especially important both in the protection of the human fetus from excessive glucocorticoid exposure, and in the protection of distal nephron mineral ocorticoid receptors from glucocorticoid exposure (14). The impairment of this conversion is thought to result in hypertension associated with renal insufficiency (15). 

Hurst (19) discusses the similarity in action of the pyrethrins and of DDT as indicated by a dispersant action on the lipids of insect cuticle and internal tissue. He has developed an elaborate theory of contact insecticidal action but provides no experimental data. Hurst believes that the susceptibility to insecticides depends partially on the cuticular permeability, but more fundamentally on the effects on internal tissue receptors which control oxidative metabolism or oxidative enzyme systems. The access of pyrethrins to insects, for example, is facilitated by adsorption and storage in the lipophilic layers of the epicuticle. The epicuticle is to be regarded as a lipoprotein mosaic consisting of alternating patches of lipid and protein receptors which are sites of oxidase activity. Such a condition exists in both the hydrophilic type of cuticle found in larvae of Calliphora and Phormia and in the waxy cuticle of Tenebrio larvae. Hurst explains pyrethrinization as a preliminary narcosis or knockdown phase in which oxidase action is blocked by adsorption of the insecticide on the lipoprotein tissue components, followed by death when further dispersant action of the insecticide results in an irreversible increase in the phenoloxidase activity as a result of the displacement of protective lipids. This increase in phenoloxidase activity is accompanied by the accumulation of toxic quinoid metabolites in the blood and tissues—for example, O-quinones which would block substrate access to normal enzyme systems. The varying degrees of susceptibility shown by different insect species to an insecticide may be explainable not only in terms of differences in cuticle make-up but also as internal factors associated with the stability of oxidase systems. 

Ticlopidine inhibits the P2Yj2 platelet ADP receptor, thus inhibiting ADP-dependent activation of the GP Ilb/IIIa receptor. It has a slow onset of action and takes 3-7 days to reach its maximal antiplatelet effect. It is inactive in vitro and must undergo activation by the hepatic cytochrome p450 enzyme system. Secondary prevention trials have found that ticlopidine-treated patients have an estimated RRR of 33% for the composite endpoint of stroke, myocardial infarction, or vascular death after ischemic stroke. Significant adverse effects include bone marrow depression, rash, diarrhea, and thrombotic thrombocytopenic purpura. No clinical trials have studied ticlopidine for the treatment of stroke in the acute phase. 

To study drug-receptor/enzyme interaction, it is not always convenient or appropriate to use a living system of the target receptor. Instead, biochemical assays can be devised to mimic the target. Very often, the assays use multicolor luminescence or fluorescence-based reagents. In this way, the reaction path can be followed in space and time to enable quantitative evaluation of the reaction. 

MecfianismofAction An antidepressant that inhibits the MAO enzyme system at central nervous system (CNS) storage sites. The reduced MAO activity causes an increased concentration in epinephrine, norepinephrine, serotonin, and dopamine at neuron receptor sites. Therapeutic Effect Produces antidepressant effect. 

Peripheral tissue markers include high-molecular-weight complex biomolecules (receptors) and enzyme systems that can be obtained from outside the CNS (e.g., in platelets, lymphocytes, skin fibroblasts, and erythrocytes) and are thought to reflect or parallel central neuronal activity. 

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