title: Plasma membrane poration by opioid neuropeptides: a possible mechanism of pathological signal transduction.
abstract: Neuropeptides induce signal transduction across the plasma membrane by acting through cell-surface receptors. The dynorphins, endogenous ligands for opioid receptors, are an exception; they also produce non-receptor-mediated effects causing pain and neurodegeneration. To understand non-receptor mechanism(s), we examined interactions of dynorphins with plasma membrane. Using fluorescence correlation spectroscopy and patch-clamp electrophysiology, we demonstrate that dynorphins accumulate in the membrane and induce a continuum of transient increases in ionic conductance. This phenomenon is consistent with stochastic formation of giant (~2.7 nm estimated diameter) unstructured non-ion-selective membrane pores. The potency of dynorphins to porate the plasma membrane correlates with their pathogenic effects in cellular and animal models. Membrane poration by dynorphins may represent a mechanism of pathological signal transduction. Persistent neuronal excitation by this mechanism may lead to profound neuropathological alterations, including neurodegeneration and cell death.
authors.affiliation: State Key Lab for Molecular Biology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors.forename: O
authors.initials: O
authors.lastname: Maximyuk
authors.affiliation: State Key Lab for Molecular Biology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors.forename: V
authors.initials: V
authors.lastname: Khmyz
authors.affiliation: Department of Clinical Neuroscience Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C-J
authors.initials: CJ
authors.lastname: Lindskog
authors.affiliation: Department of Clinical Neuroscience Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: V
authors.initials: V
authors.lastname: Vukojević
authors.affiliation: State Key Lab for Molecular Biology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors.forename: T
authors.initials: T
authors.lastname: Ivanova
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Bazov
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
authors.forename: K F
authors.initials: KF
authors.lastname: Hauser
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Bakalkin
authors.affiliation: State Key Lab for Molecular Biology, Bogomoletz Institute of Physiology, Kiev, Ukraine.
authors.forename: O
authors.initials: O
authors.lastname: Krishtal
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D004399:Dynorphins / Q000008:administration & dosage / Q000378:metabolism; D004723:Endorphins / Q000008:administration & dosage / Q000378:metabolism; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D018613:Microscopy, Confocal; D009479:Neuropeptides / Q000008:administration & dosage / Q000378:metabolism*; D018847:Opioid Peptides / Q000008:administration & dosage / Q000378:metabolism*; D016716:PC12 Cells; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D004723:Endorphins; D004745:Enkephalins; D008024:Ligands; D009479:Neuropeptides; D018847:Opioid Peptides; D011498:Protein Precursors; D004399:Dynorphins; C036200:rimorphin; C033660:preproenkephalin