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Perturbations of model membranes induced by pathogenic dynorphin A mutants causing neurodegeneration in human brain
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2011 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 411, no 1, 111-114 p.Article in journal (Refereed) Published
Abstract [en]

Several effects of the endogenous opioid peptide dynorphin A (Dyn A) are not mediated through the opioid receptors. These effects are generally excitatory, and result in cell loss and induction of chronic pain and paralysis. The mechanism(s) is not well defined but may involve formation of pores in cellular membranes. In the 17-amino acid peptide Dyn A we have recently identified L5S, R6W, and R9C mutations that cause the dominantly inherited neurodegenerative disorder Spinocerebellar ataxia type 23. To gain further insight into non-opioid neurodegenerative mechanism(s), we studied the perturbation effects on lipid bilayers of wild type Dyn A and its mutants in large unilamellar phospholipid vesicles encapsulating the fluorescent dye calcein. The peptides were found to induce calcein leakage from uncharged and negatively charged vesicles to different degrees, thus reflecting different membrane perturbation effects. The mutant Dyn A R6W was the most potent in producing leakage with negatively charged vesicles whereas Dyn A L5S was virtually inactive. The overall correlation between membrane perturbation and neurotoxic response [3] suggests that pathogenic Dyn A actions may be mediated through transient pore formation in lipid domains of the plasma membrane.

Place, publisher, year, edition, pages
2011. Vol. 411, no 1, 111-114 p.
Keyword [en]
Prodynorphin, Dynorphin A, Spinocerebellar ataxia, Non-opioid activity, Large unilamellar vesicle, Calcein leakage
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-157260DOI: 10.1016/j.bbrc.2011.06.105ISI: 000293368000019OAI: oai:DiVA.org:uu-157260DiVA: diva2:436011
Available from: 2011-08-22 Created: 2011-08-22 Last updated: 2011-08-22Bibliographically approved

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