Post-receptor effects

Post-receptor effects are still controversial. Kolterman and Olefsky (1984) felt that an increase in post-receptor function appears to be a crucial determinant of the clinical response to sulphonylureas (Fig. 23). Extra-pancreatic mechanisms in obese NIDDM patients may vary with the... 

Administration of dipyridamole-AMP to mice 5—25 min after 1 Gy (100 rad) of TBI y-kradiation is also protective, as indicated by plasma thymidine levels and the amount of saline soluble polynucleotides in the thymus (112). Adding dipyridamole-AMP to in vitro kradiated suspensions of thymocytes enhances the rejoining of DNA strand breaks (112). These post-kradiation effects ate presumably mediated by the activation of extraceUulat adenosine receptors. 

The first identified Ascaris FaRP, AF1 (KNEFIRFamide), and the structurally related peptide, AF2 (KHEYLRFamide), have been found to inhibit locomotory waves when injected into adult worms (Cowden et al., 1989 Cowden and Stretton, 1993). Their effects on body-wall muscle strips are biphasic, comprising a transient relaxation followed by an extended period of increased contractile activity (Maule et al., 1995b Bowman et al., 1996). When using muscle strips that have had the motor nerve cords removed, only the inhibitory actions of AF1 and AF2 are seen (Maule et al., 1995b). This suggests that the inhibitory phase is due to post-synaptic effects on body-wall muscle in the worm. In contrast, the excitatory effects are nerve-cord dependent and are not observed in muscle strips that have been denervated. Another possibility is that the peptides interact with receptors at the post-synaptic junction - these are also removed in specimens that have had the motor nerve cords removed. 

What are the mechanisms by which trichothecenes exert their transcriptional and post-transcriptional effects The 60S ribosomal subunit is a well-known molecular target of trichothecenes in leukocytes and other actively proliferating eukaryotic cells,3 whereas attempts to demonstrate alternative receptors have not been successful.37 38 Translational inhibitors that bind to ribosomes rapidly activate mitogen-activated protein kinases (MAPKs) and apoptosis via a mechanism termed the ribotoxic stress response. 39-40... 

Drug distribution does not constitute the sole explanation for the appearance of a counter-clockwise hysteresis. Another reason may be that once the drug has reached its site of action, the cascade of receptor-related and post-receptor events leading to the measured drug effect takes time to develop and lags... 

I-BOP-induced aortic contractions were decreased 50% in dexamethasone-treated rabbits, and this functional effect of corticosteroid administration was accompanied by an 25% reduction in aortic cell membrane TP receptor number (186). Although the functional and receptor changes were corrrelated, the magnitude of the reduction in receptor density was small. It is possible that the effects of corticosteroids on aortic contraction were due to an influence on post-receptor events as well as on receptors (186). 

The majority of Type-II diabetics are obese (II b) and suffer predominantly from an impairment of insulin action due to heterogeneous mechanisms. Decreased insulin responsiveness of peripheral tissues may be due to (1) a post-receptor defect with secondary hyperinsulinaemia, (2) down-regulation of the number of insulin receptors, or (3) the glucotoxic effect of hyper-glycaemia caused by accelerated hepatic glucose production. An additional impairment of insulin secretion is present, however, only in non-obese Type-II-a diabetics. 

The current preferred postulated mechanism of vanadium s in vitro effects is that vanadate stimulates specific protein-tyrosine phosphorylation by virtue of its inhibitory actions on appropriate PTPases. Routine addition of vanadate to cell lysates, particularly for tyrosine kinase assays, is testimony of the ability of vanadate to preserve the phosphotyrosine content of cells. The preponderance of evidence favors a post-receptor mechanism in stimulating glucose utilization, perhaps also involving a cytosolic i.e. non-receptor) protein tyrosine kinase that is stimulated preferentially by vanadium and may be insulin independent. Vanadyl is not a potent PTPase inhibitor. " Thus, whatever portion of intracellular vanadium is present as vanadyl is probably acting by some alternative mechanism. ... 

On the other hand, berberine is also able to induce the expressirui of insulin receptors (at least in liver) in a dose-dependent manner, through upregulation of insulin receptor mRNA [28, 29]. This effect was dependent on the presence of insulin. Berberine has also been linked to improving post-receptor signal transduction [24]. 

Leff S, Adams L, Hyttel J, Creese I (1981) Kainate lesion dissociates striatal dopamine receptor radioligand binding sites. Eur J Pharmacol 70 71-75 Lehmann J, Langer S (1982) Dopamine autoreceptors differ pharmacologically from post-synaptic dopamine receptors Effect of (-)-N-(2-chloroethyl)-norapomorphine. Eur J Pharmacol 77 85-86... 

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