Perturbations of model membranes induced by pathogenic dynorphin A mutants causing neurodegeneration in human brain

• Published in: Biochemical and biophysical research communications Vol. 411; no. 1; pp. 111 - 114
• Main Authors: Madani, Fatemeh, Taqi, Malik Mumtaz, Wärmländer, Sebastian K.T.S., Verbeek, Dineke S., Bakalkin, Georgy, Gräslund, Astrid
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.07.2011
• Subjects: Amino Acid Sequence; Brain; Brain - metabolism; Calcein; Calcein leakage; Cell Membrane - metabolism; Dynorphin A; Dynorphins - genetics; Fluorescent indicators; Humans; Large unilamellar vesicle; Leakage; Lipid bilayers; Lipid rafts; MEDICIN; MEDICINE; Molecular Sequence Data; Mutation; Neurodegenerative diseases; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neurotoxicity; Non-opioid activity; Opioid receptors; Pain; Paralysis; Phospholipids; Plasma membranes; Pores; Prodynorphin; Spinocerebellar ataxia; Vesicles; Dynorphin A; Prodynorphin; Large unilamellar vesicle; Calcein leakage; Spinocerebellar ataxia; Non-opioid activity
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2011.06.105

► Dynorphin A neuropeptides cause leakage in model membranes. ► Model membranes are unilamellar phospholipid vesicles with encapsulated calcein. ► Degree of leakage varies for dynorphin A mutants R6W, R9C and L5S. ► Vesicle leakage correlates with neurotoxicity of dynorphin A mutants. 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.