Interference with second messenger

Interference with signal transduction by reducing second-messenger synthesis through. 

The second popular hypothesis for the therapeutic mechanism of action of Li+ is its interference with another receptor-coupled, second messenger system, that of the plasma-membrane bound enzyme, adenylate... 

The effects of Li+ upon this system have been reviewed in depth by Mork [131]. Animal studies originally demonstrated that Li+ inhibits cAMP formation catalyzed by adenylate cyclase in a dose-dependent manner [132]. The level of cAMP in the urine of manic-depressive patients changes with mental state, being abnormally elevated during the switch period between depression and mania it is proposed that Li+ s inhibitory effect upon adenylate cyclase activity may correct this abnormality. Subsequent research, in accord with the initial experiments, have shown that Li+ s interference with this second messenger system involves more than one inhibitory action. At therapeutic levels, Li+ inhibits cAMP accumulation induced by many neurotransmitters and hormones, both in... 

Its mechanism of action is not well understood. Some possible actions include inhibition of norepinephrine release and increased re-uptake of norepinephrine and serotonin. It also possibly increases the synthesis and turnover of serotonin. Lithium interferes with the production and release of the second messengers phosphatdylinositol-4,5-bisphosphate and diacyl glycerol. Finally it may uncouple receptor recognition sites from GTP-binding protein by competing with Mg++. 

Cholera toxin interferes with the function of a key G-protein in the small intestine by deactivating its intrinsic GTPase activity. The consequence is uncontrolled activation of the signal transduction pathway which produces the second messenger 3, 5 -cyclic AMP leading to a life-threatening diarrhea following the activation of ion and water secretion. 

Fig. 8. Effects of cannabinoids on synaptic transmission. Activation ofthe CBq receptor at the presynaptic axon terminal inhibits transmitter release from the synaptic vesicle. Three mechanisms can be involved in presynaptic inhibition X refers to unknown second messengers) inhibition of voltage-dependent calcium channels, activation of potassium channels and direct interference with the vesicle release machinery.TheCBi receptor can be activated by exogenous agonists, but also by the endocannahinoids anandamide (A 4) and 2-arachidonoylglycerol (2-AG i, which are released from the postsynaptic neuron by passive and/or facilitated diffusion. The synthesis of endocannahinoids is triggered by a depolarisation-induced ( / , membrane potential) calcium influx or by activation ofGq/n protein-coupled receptors...

Disruption of Ca Homeostasis and Neurological Effects. Neurological and/or neurodevelopmental effects from exposure to PCBs also have been hypothesized to involve interference with calcium homeostatic mechanisms and intracellular second messenger systems by PCB congeners that are not effective Ah receptor agonists (see reviews by Kodavanti and Tilson 1997 Tilson and Kodavanti 1998 Tilson et al. 1998). In agreement with structure-activity relationships observed for PCB effects on dopamine levels in pheochromocytoma cells (Shain et al. 1991), 2,2 -diCB altered intracellular calcium homeostasis in cultured rat cerebellar granule cells (increased free calcium levels and inhibited calcium... 

Lithium is similar to sodium in that it forms positive ions (Li+) and can pass through sodium ion channels in neuronal cell membranes. It tends to accumulate inside neurons and may interfere with nerve action potentials or the activation of second messenger systems within the neuron (see Chapter 3, page 63). In addition, lithium may inhibit the release of monoamines from nerve endings and increase their uptake. However, the exact mode of action of lithium in affective disorders is unknown. 

It may be argued that morphogenetic factors regulate early embryo-genesis by interference with quite different processes. Binding of the factors to cytoplasmic membranes could lead to an activation of membrane-bound adenylcyclase and a release of cyclic adenylate as a second messenger (for reference see Sutherland et al., 1965 Jost and Rickenberg,... 

A number of criteria were defined to establish whether a hormonal effect is mediated through cAMP. First, the concentration of cAMP must rise before hormonal effects become apparent. Second, the response of the target tissue must be proportionate to the amount and the biological activity of the primary messenger. Third, antagonists to a hormone that raises cAMP should reduce the levels of cAMP. Fourth, inhibitors of those enzymes that interfere with cAMP breakdown should enhance the hormonal effect. 

Somatostatin is thought to act through an inhibitory G protein to interfere with receptor-mediated second messenger production, explaining the inhibition of histamine stimulation. In the case of EGF, the inhibition appears to occur at a site beyond the Hz receptor, because EGF also inhibits dibutyryl cAMP stimulation of acid formation. The PG EP3 receptor has been shown to reduce cAMP levels, and, presumably, bonding to this receptor by relatively nonselective PGEz compounds accounts for their inhibition of acid secretion. 

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