Subject platelet receptor

Both clinical and experimental studies have shown that a number of transmitter receptors and amine transport processes show circadian changes. It is well established that depression is associated with a disruption of the circadian rhythm as shown by changes in a number of behavioural, autonomic and neuroendocrine aspects. One of the main consequences of effective treatment is a return of the circadian rhythm to normality. For example, it has been shown that the 5-HT uptake into the platelets of depressed patients is largely unchanged between 0600 and 1200 hours, whereas the 5-HT transport in control subjects shows a significant decrease over this period. The normal rhythm in 5-HT transport is only reestablished when the depressed patient responds to treatment. Thus it may be hypothesized that the mode of action of antidepressants is to normalize disrupted circadian rhythms. Only when the circadian rhythm has returned to normal can full clinical recovery be established. 

Most, but not all, platelet radioligand studies in medication-free patients with major depressive disorder have found a significant increase in the number of this receptor s binding sites compared with control subjects. 

The insulin receptor is the prototype for a number of receptor enzymes with a similar structure and receptor Tyr kinase activity. The receptors for epidermal growth factor and platelet-derived growth factor, for example, have structural and sequence similarities to the insulin receptor, and both have a protein Tyr kinase activity that phosphorylates IRS-1. Many of these receptors dimerize after binding ligand the insulin receptor is already a dimer before insulin binds. The binding of adaptor proteins such as Grb2 to (P) Tyr residues is a common mechanism for promoting protein-protein interactions, a subject to which we return in Section 12.5. 

Hyperserotonemia has been a consistent finding in subjects with autism, which may be due to activity of serotonin-associated platelet proteins (Hranilovic et al., 2008, 2009). Interestingly, 99% of blood serotonin is contained in platelets (Anderson et al., 1987) and studies have shown that there is an approximate 50% increase in blood-levels of serotonin in subjects with autism vs. controls (McBride et al., 1998). Hypotheses for increased serotonin include increased synthesis of serotonin by tryptophan hydroxylase (TPHl), increased uptake of serotonin into platelets via serotonin transporters (5-HTT), diminished release of serotonin from platelets via serotonin 2A receptor, and decreased breakdown of serotonin by monoamine oxidase (MAOA) (Hranilovic et al., 2008). A study by Hranilovic et al. (2008) identified polymorphisms of tryptophan hydroxylase and MAOA with increased serum serotonin levels. Similarly, haplotype analysis has shown a significant association between polymorphisms of TPHl and increased serotonin in whole blood (Cross et al., 2008). 

Other human subjects with defective TP receptor agonist-stimulated platelet aggre-gation have been described (70-73), but a specific signal transduction abnormality has been defined in only one individual (73). 

Children with nephrotic syndronre were found to have elevated excretion of TXBj, and the TP receptor agonist, STAj, stimulated a greater calcium flux in their platelets than in platelets fiom control subjects or from patients with nephrotic syndome who were in ronission (241). TP receptor binding was not studied, and the mechanism responsible for the accentuated response to STAj was not defined. 

The methylxanthines, theophylline and caffeine, act primarily as antagonists for both adenosine A, and Aj receptors (65-68). Caffeine is a relatively weak adenosine antagonist as compared to foeophylline (69). Studies to examine these methylxanthines as adenosine antagonists on platelet ftinction have been limited. Both theophylline and caffeine are shown to stimulate platelet reactivity in vitro and in vivo studies (49,50,67,69,70). Platelets from subjects after chronic consumption of caffeine show decreased antiplatelet activity of the adenosine analog NECA on thrombin-induced... 

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