Acts in different tissues through interaction to nicotinic acetylcholine receptors (nAChRs). In brain, isoform 2 modulates functional properties of nAChRs to prevent excessive excitation, and hence neurodegeneration. Enhances desensitization by increasing both the rate and extent of desensitization of alpha(4)beta(2) nAChRs and slowing recovery from desensitization. Promotes large amplitude ACh-evoked currents through alpha(4)beta(2) nAChRs (By similarity). Prevents plasticity in the primary visual cortex late in life (By similarity). In keratinocytes, isoform 3 delays differentiation and prevents apoptosis.
The biologic role of novel cholinergic toxin-like signaling peptides termed SLURP (secreted mammalian Ly-6/uPAR-related protein) in the mucocutaneous epithelium is a subject of intense research. Previous studies demonstrated that SLURP-1 activates the alpha7 subtype of keratinocyte nicotinic acetylcholine receptors (nAChRs) and facilitates keratinization and programmed cell death, and that the level of SLURP-2 was found to be upregulated several fold in the hyperproliferative skin of patients with psoriasis. In this study, we demonstrated for the first time that human epidermal and oral keratinocytes secrete SLURP-2. We cloned human SLURP-2 and produced the mouse monoclonal antibody 341F10-1F12 that visualized SLURP-2 in the cytoplasm of normal human epidermal and oral keratinocytes grown in culture. In epidermis, SLURP-2 was found predominantly in the suprabasal compartment, whereas in the attached gingiva-in the lowermost epithelial layers. Recombinant SLURP-2 (rSLURP-2) competed with nicotinic radioligands for binding to keratinocytes, showing a higher affinity to the [3H]epibatidine- than [3H]nicotine-labeled sites. Treatment with rSLURP-2 significantly (P < 0.05) increased the number of keratinocytes in culture and their resistance to apoptosis, which could be abolished by mecamylamine more efficiently than alpha-bungarotoxin. By real-time PCR and in-cell western, rSLURP-2 significantly (P < 0.05) downregulated gene expression of the differentiation markers loricrin, filaggrin, and cytokeratins 1 and 10, and pro-apoptotic Bax, Bad, and caspase 3 which were elevated by high extracellular calcium, and rSLURP-2 also abolished activation of caspases 3 and 8 caused by camptothecin. These results indicated that SLURP-2 competes with acetylcholine predominantly at the alpha3 nAChR, and that receptor ligation with SLURP-2 delays keratinocyte differentiation and prevents apoptosis. Thus, the different effects observed for SLURP-1 and -2 can be explained by their differential binding to the nAChR subtypes expressed in keratinocytes. These findings present a novel paradigm of the physiologic regulation of mucocutaneous epithelial cells by locally produced small hormone-like peptide molecules, and open novel directions toward better understanding and treating of skin and mucosal diseases.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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