Rotein composition of lipid rafts purified from AY9944-treated rat brain tissue is altered. Analyses of distinct receptor systems have shown dysfunction in SLOS model systems. Dhcr7 mutant mast cells demonstrate constitutive cytokine release and hyper-degranulation immediately after stimulation in the higher affinity IgE receptor (138). These defects appear to result from displacement of Fyn kinase from lipid rafts containing 7DHC plus a resulting enhance in Fyn kinase activity and Akt phosphorylation (138). Neurophysiological studies have demonstrated that frontal cortex neurons from Dhcr7 mutant embryos have an impaired N-methyl-D-aspartic acid receptor response to glutamate stimulation (127). 7DHC can’t substitute forcholesterol in restoring ligand binding to solubilized hippocampal serotonin1A receptors (139), and serotonin1A receptor signaling is impaired in AY9944-treated cells (140). These in vitro findings may perhaps be mechanistically associated to the observation by Waage-Baudet et al. (141) of abnormal serotonergic development in Dhcr7 mutant embryos and are in particular intriguing offered the higher frequency of autistic symptoms in SLOS individuals (53, 56). Alteration with the sterol composition also appears to alter other physiochemical properties of membranes. Gondr ewis et al. (142) located, in comparison to cholesterol, that 7DHC decreases the bending rigidity and intrinsic curvature of artificial membranes. This observation may possibly clarify abnormal pancreatic secretory granule formation (142). As well as altered PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19957072 sterol composition, Pappu et al. (143) demonstrated enhanced levels of dolichol and ubiquinone synthesis in SLOS and postulated that these nonsterol isoprenoids could alter membrane fluidity, permeability, and function. In addition to its structural function in cellular membranes, cholesterol is often a precursor for the synthesis of steroids, neuroactive steroids, oxysterols, and bile acids. Hence, in SLOS, there may perhaps be a deficiency of the typical cholesterolderived metabolites or formation of DHC-derived analogs. Both 7DHC and 8DHC can enter the cholesterol biosynthetic pathway, and dehydrocholesterol analogs of pregnenolone, pregnanetriol, dehydroepiandrosterone, and androstenediol have already been identified in SLOS patients (14446). As noted above (SLOS diagnosis and therapy section), these DHC-derived steroids is often used for the prenatal diagnosis of SLOS. The identified dehydrosteroids and dehydrosteroid metabolites suggest that dehydrocholesterol can be transported in to the mitochondria and take part in the following enzymatic reactions: p450 side chain cleavage, 17-hydroxylase/17,20-lyase, three -hydroxysteroid dehydrogenase, three -hydroxysteroid dehydrogenase, 17 -hydroxysteroid dehydrogenase, 20 hydroxysteroid dehydrogenase, and five -reductase (144). A 7DHC derived analog of allopregnanolone, 7-dehydroallopregnanolone, has also been identified in urine from postpubertal, female SLOS individuals (101). Allopregnanolone can be a neuroactive steroid. Neuroactive steroids are modulatory ligands for neurotransmitter and SPDP nuclear steroid hormone receptors and have functional roles in neurogenesis, neuroprotection, and myelination (147). It truly is not identified to what degree the steroids synthesized from dehydrocholesterol have biological activity. It really is plausible that these DHC-derived steroid analogs have either antagonist or agonistic activity and could functionally contribute for the SLOS cognitive or behavioral phenotype. In contrast to cholesterol, neuroactive steroids can cros.
