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J. Biol. Chem., Vol. 280, Issue 28, 26360-26370, July 15, 2005

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Translocation of Dynorphin Neuropeptides across the Plasma Membrane

A PUTATIVE MECHANISM OF SIGNAL TRANSMISSION^*

Zoya Marinova,^ab Vladana Vukojevi,^ab Slavina Surcheva,^c Tatiana Yakovleva,^a Gvido Cebers,^d Natalia Pasikova,^a Ivan Usynin,^a Loïc Hugonin,^e Weijie Fang,^f Mathias Hallberg,^g Daniel Hirschberg,^h Tomas Bergman,^h Ülo Langel,ⁱ Kurt F. Hauser,^j Aladdin Pramanik,^h Jane V. Aldrich,^f Astrid Gräslund,^e Lars Terenius,^a and Georgy Bakalkin^ak

From the ^aSection of Alcohol and Drug Dependence Research, Department of Clinical Neuroscience, Karolinska Institute, S-17176 Stockholm, Sweden, the ^cDepartment of Pharmacology, Medical Faculty, Medical University, 1431 Sofia, Bulgaria, ^dGeneral Toxicology Sc, Safety Assessment, Astra Zeneca R & D Södertälje, SE-15185 Södertälje, Sweden, the ^eDepartment of Biochemistry and Biophysics, Arrhenius Laboratories, Stockholm University, SE-10691 Stockholm, Sweden the ^fDepartment of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas 66045, the ^gDepartment of Pharmaceutical Biosciences, Uppsala University, SE-75124 Uppsala, Sweden, the ^hDepartment of Medical Biochemistry and Biophysics, Karolinska Institute, SE-17176 Stockholm, Sweden, the ⁱDepartment of Neurochemistry and Neurotoxicology, Arrhenius Laboratories, Stockholm University, Stockholm, SE-10691 Sweden, and the ^jDepartment of Anatomy and Neurobiology University of Kentucky, College of Medicine, Lexington, Kentucky 40536-0298

Several peptides, including penetratin and Tat, are known to translocate across the plasma membrane. Dynorphin opioid peptides are similar to cell-penetrating peptides in a high content of basic and hydrophobic amino acid residues. We demonstrate that dynorphin A and big dynorphin, consisting of dynorphins A and B, can penetrate into neurons and non-neuronal cells using confocal fluorescence microscopy/immunolabeling. The peptide distribution was characterized by cytoplasmic labeling with minimal signal in the cell nucleus and on the plasma membrane. Translocated peptides were associated with the endoplasmic reticulum but not with the Golgi apparatus or clathrin-coated endocytotic vesicles. Rapid entry of dynorphin A into the cytoplasm of live cells was revealed by fluorescence correlation spectroscopy. The translocation potential of dynorphin A was comparable with that of transportan-10, a prototypical cell-penetrating peptide. A central big dynorphin fragment, which retains all basic amino acids, and dynorphin B did not enter the cells. The latter two peptides interacted with negatively charged phospholipid vesicles similarly to big dynorphin and dynorphin A, suggesting that interactions of these peptides with phospholipids in the plasma membrane are not impaired. Translocation was not mediated via opioid receptors. The potential of dynorphins to penetrate into cells correlates with their ability to induce non-opioid effects in animals. Translocation across the plasma membrane may represent a previously unknown mechanism by which dynorphins can signal information to the cell interior.

Received for publication, November 4, 2004 , and in revised form, May 12, 2005.

^* This work was supported by research grants from the Swedish Research Council (to Ü. L., A. P., A. G., L. T., and G. B.), the AFA Foundation (to G. B.), the Wenner-Gren Foundations (to V. V.), the Swedish Institute (to Z. M. and S. S.), the Novo-Nordic Foundation (to A. P.), and European Commission Contracts HPRN-CT-2001-00242 and QLK3-CT-2002-01989 (to Ü. L. and A. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^b Both authors contributed equally to this work.

^k To whom correspondence should be addressed: Section of Alcohol and Drug Dependence Research, Dept. of Clinical Neuroscience, Karolinska Institute, S-17176, Stockholm, Sweden. Tel.: 46-8-5177-5751; Fax: 46-8-5177-6180; E-mail: Georgy.Bakalkin{at}cmm.ki.se.

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