Misprocessing and mislocalization of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) has been described for the major CF-causing mutation (delta F508) in heterologous expression systems in vitro. We have generated monoclonal antibodies (mAbs) to CFTR with the aim of localizing the protein and its CF variants in vivo. Of the tissues where CFTR was observed, only the sweat gland is readily available and does not undergo secondary changes due to CF disease pathology. Sweat ducts from CF patients homozygous for delta F508 did not show the typical apical membrane staining seen in control biopsies. This demonstrates that the biosynthetic arrest and intracellular retention of delta F508 CFTR initially observed in vitro does occur in vivo and emphasizes the need to focus efforts on understanding the mislocalization.
The design, synthesis and pharmacological evaluation of a novel class of Dmt-Tic dipeptide analogues are described. These resulting analogues bearing different C-terminal functionalities were found to bind to the human delta receptor with high affinity. One specific class of dipeptides bearing urea/thiourea functionalities showed partial to full activation of the delta receptor. Several dipeptides also showed good binding affinities with full activation of the human kappa receptor, a novel property for those ligands.
We have prepared a XgtlO cDNA library with the mRNA isolated from fetal calf brains which were actively myelinating. Using two oligonucleotides made according to the known amino acid sequence of myelin proteolipid protein (PLP or lipophilin), we have isolated several cDNA clones for this major intrinsic membrane protein of myelin. One of these clones, designated as pLPl, is found to contain 444 bp of coding sequence for the C-terminal half of PLP and 486 bp of 3' untranslated sequence. Using pLPl as a hybridization probe, we have studied the regulation of PLP at the mRNA level during rat brain development. Our results show that the relative amounts of mRNA for PLP and that for the major extrinsic protein of the myelin membrane, myelin basic protein, increase coordinately during the course of myelination in the brain.
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