Cell-Penetrating Mimics of Agonist-Activated G-Protein Coupled Receptors

Springer Science and Business Media LLC - Tập 11 - Trang 237-247 - 2005
Pernilla Östlund1, Kalle Kilk2, Maria Lindgren1, Mattias Hällbrink1, Yang Jiang1, Metka Budihna3, Katarina Cerne3, Aljosa Bavec4, Claes-Göran Östenson5, Matjaz Zorko4, Ülo Langel1
1Department of Neurochemistry and Neurotoxicology, Stockholm University, Stockholm, Sweden
2Centre of Molecular and Clinical Medicine, University of Tartu, Tartu, Estonia
3Institute of Pharmacology and Experimental Toxicology, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
4Institute of Biochemistry, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
5Department of Molecular Medicine, Endocrine and Diabetes Unit, Karolinska Hospital, Stockholm, Sweden

Tóm tắt

Cell-penetrating peptides have proven themselves as valuable vectors for intracellular delivery. Relatively little is known about the frequency of cell-penetrating sequences in native proteins and their functional role. By computational comparison of peptide sequences, we recently predicted that intracellular loops of G-protein coupled receptors (GPCR) have high probability for occurrence of cell-penetrating motifs. Since the loops are also receptor and G-protein interaction sites, we postulated that the short cell-penetrating peptides, derived from GPCR, when applied extracellularly can pass the membrane and modulate G-protein activity similarly to parent receptor proteins. Two model systems were analyzed as proofs of the principle. A peptide based on the C-terminal intracellular sequence of the rat angiotensin receptor (AT1AR) is shown to internalize into live cells and elicit blood vessel contraction even in the presence of AT1AR antagonist Sar1-Thr8-angiotensin II. The peptide interacts with the same selectivity towards G-protein subtypes as agonist-activated AT1AR and blockade of phospholipase C abolishes its effect. Another cell-penetrating peptide, G53-2 derived from human glucagon-like peptide receptor (GLP-1R) is shown to induce insulin release from isolated pancreatic islets. The mechanism was again found to be shared with the original GLP-1R, namely G11-mediated inositol 1,4,5-triphosphate release pathway. These data reveal a novel possibility to mimic the effects of signalling transmembrane proteins by application of shorter peptide fragments.

Tài liệu tham khảo

L. L. Baggio D. J. Drucker (2004) Best Pract. Res. Clin. Endocrinol. Metab. 18 IssueID4 531–554 Occurrence Handle10.1016/j.beem.2004.08.001 Occurrence Handle15533774 Occurrence Handle1:CAS:528:DC%2BD2cXpsVOltrs%3D A. Bavec M. Hällbrink Ü. Langel M. Zorko (2003) Regul. Pept. 111 IssueID1–3 137–144 Occurrence Handle12609761 Occurrence Handle1:CAS:528:DC%2BD3sXhsVCmsLo%3D J. E. Bleasdale N. R. Thakur R. S. Gremban G. L. Bundy F. A. Fitzpatrick R. J. Smith S. Bunting (1990) J. Pharmacol. Exp. Ther. 255 IssueID2 756–768 Occurrence Handle2147038 Occurrence Handle1:CAS:528:DyaK3MXjvF2gsA%3D%3D R. K. Bommakanti E. A. Dratz D. W. Siemsen A. J. Jesaitis (1995) Biochemistry 34 IssueID20 6720–6728 Occurrence Handle10.1021/bi00020a017 Occurrence Handle7756303 Occurrence Handle1:CAS:528:DyaK2MXls1yrsLs%3D M. Brede L. Hein (2001) Regul. Pept. 96 IssueID3 125–132 Occurrence Handle10.1016/S0167-0115(00)00168-3 Occurrence Handle11111018 Occurrence Handle1:CAS:528:DC%2BD3cXosFeqt74%3D D. Cassel Z. Selinger (1976) Biochim. Biophys. Acta 452 IssueID2 538–551 Occurrence Handle188466 Occurrence Handle1:CAS:528:DyaE2sXjvFansQ%3D%3D S. Conchon M. B. Barrault S. Miserey P. Corvol E. Clauser (1997) J. Biol. Chem. 272 IssueID41 25566–25572 Occurrence Handle10.1074/jbc.272.41.25566 Occurrence Handle9325274 Occurrence Handle1:CAS:528:DyaK2sXms1Gjt74%3D G. P. Dietz M. Bähr (2004) Mol. Cell. Neurosci. 27 IssueID2 85–131 Occurrence Handle10.1016/j.mcn.2004.03.005 Occurrence Handle15485768 Occurrence Handle1:CAS:528:DC%2BD2cXos1Kksb4%3D J. S. Dillon Y. Tanizawa M. B. Wheeler X. H. Leng B. B. Ligon D. U. Rabin H. Yoo-Warren M. A. Permutt A. E. Boyd Suffix3rd (1993) Endocrinology 133 IssueID4 1907–1910 Occurrence Handle10.1210/en.133.4.1907 Occurrence Handle8404634 Occurrence Handle1:CAS:528:DyaK2cXps1Sgtg%3D%3D L. Franzoni G. Nicastro T. A. Pertinhez M. Tato C. R. Nakaie A. C. Paiva S. Schreier A. Spisni (1997) J. Biol. Chem. 272 IssueID15 9734–9741 Occurrence Handle9092505 Occurrence Handle1:CAS:528:DyaK2sXisFOkt7g%3D C. Galera F. Clemente A. Alcantara M. A. Trapote A. Perea M. I. Lopez-Delgado M. L. I. Villanueva-Penacarrillo Valverde (1996) Cell Biochem. Funct. 14 IssueID1 43–48 Occurrence Handle8907253 Occurrence Handle1:CAS:528:DyaK28XhsVSnsbY%3D R. Göke J. M. Conlon (1988) J. Endocrinol. 116 IssueID3 357–362 Occurrence Handle2832504 R. Göke M. E. Trautmann E. Haus G. Richter H. C. Fehmann R. Arnold B. Goke J. M. Conlon (1989) Am. J. Physiol. 257 IssueID3 Pt 1 G397–G401 Occurrence Handle2551182 T. L. Goodfriend M. E. Elliott K. J. Catt (1996) ArticleTitleAngiotensin receptors and their antagonists N. Engl. J. Med. 334 IssueID25 1649–1654 Occurrence Handle10.1056/NEJM199606203342507 Occurrence Handle8628362 Occurrence Handle1:CAS:528:DyaK28Xkt1emur0%3D M. Hällbrink T. Holmqvist M. Olsson C. G. Östenson S. Efendic Ü. Langel (2001) Biochim. Biophys. Acta. 1546 IssueID1 79–86 Occurrence Handle11257510 Hällbrink, M., Kilk, K., Elmquist, A., Lundberg, P., Lindgren, M., Jiang, Y., Soomets, U. and Langel, Ü.: 2005, Int. J. Pept. Res. Ther. 11(4). Hällbrink, M., Pooga, M., Metsis, M., Kogerman, P., Valkna, A., Meikas, A., Lindgren, M., Gräslund, A., Eriksson, G., Östenson, C. G., Budihna, M. V., Zorko, M., Elmquist, A., Soomets, U., Lundberg, P., Järver, P., Saar, K., El-Andaloussi, S., Kilk, K. and Langel, Ü.: 2003, Cell Penetrating Peptides, CePeP AB, Sweden. R. S. Heller T. J. Kieffer J. F. Habener (1996) Biochem. Biophys. Res. Commun. 223 IssueID3 624–632 Occurrence Handle10.1006/bbrc.1996.0945 Occurrence Handle8687446 Occurrence Handle1:CAS:528:DyaK28XjvFCrtbY%3D V. Herbert K. S. Lau C. W. Gottlieb S. J. Bleicher (1965) J. Clin. Endocrinol. Metab. 25 IssueID10 1375–1384 Occurrence Handle5320561 Occurrence Handle1:CAS:528:DyaF2MXltVSmtL0%3D J. Howl S. Jones M. Farquhar (2003) Chembiochem 4 IssueID12 1312–1316 Occurrence Handle10.1002/cbic.200300694 Occurrence Handle14661273 Occurrence Handle1:CAS:528:DC%2BD3sXpvFartr0%3D T. Inagami (1999) J. Am. Soc. Nephrol. 10 IssueIDSuppl 11 S2–S7 Occurrence Handle9892133 Occurrence Handle1:CAS:528:DyaK1MXmvFSiug%3D%3D I. Japelj M. V. Budihna L. Stanovnik I. Krisch (1999) Eur. J. Pharmacol. 369 IssueID1 43–47 Occurrence Handle10.1016/S0014-2999(99)00049-7 Occurrence Handle10204680 Occurrence Handle1:CAS:528:DyaK1MXhvVCmtrs%3D O. H. Lowry N. J. Rosebrough A. L. Farr R. J. Randall (1951) J. Biol. Chem. 193 IssueID1 265–275 Occurrence Handle14907713 Occurrence Handle1:CAS:528:DyaG38XhsVyrsw%3D%3D M. Lu M. B. Wheeler X. H. Leng A. E. Boyd Suffix3rd (1993) Endocrinology 132 IssueID1 94–100 Occurrence Handle8380389 Occurrence Handle1:CAS:528:DyaK3sXhtFOit7Y%3D P. E. MacDonald W. El-Kholy M. J. Riedel A. M. Salapatek P. E. Light M. B. Wheeler (2002) Diabetes 51 IssueIDSuppl 3 S434–S442 Occurrence Handle12475787 Occurrence Handle1:CAS:528:DC%2BD38XpsVagtb0%3D L. Marquez M. A. Trapote M. A. Luque I. Valverde M. L. Villanueva-Penacarrillo (1998) Cell Biochem. Funct. 16 IssueID1 51–56 Occurrence Handle9580153 Occurrence Handle1:CAS:528:DyaK1cXhs1yntbk%3D S. K. Mathi Y. Chan X. Li M. B. Wheeler (1997) Mol. Endocrinol. 11 IssueID4 424–432 Occurrence Handle10.1210/me.11.4.424 Occurrence Handle9092794 Occurrence Handle1:CAS:528:DyaK2sXitF2gtrs%3D F. R. McKenzie (1992) Basic Techniques to Study G-protein Function. Signal Transduction. A Practical Approach. G. Milligan Oxford University Press Oxford/New York/Toronto C. Montrose-Rafizadeh P. Avdonin M. J. Garant B. D. Rodgers S. Kole H. Yang M. A. Levine W. Schwindinger M. Bernier (1999) Endocrinology 140 IssueID3 1132–1140 Occurrence Handle10.1210/en.140.3.1132 Occurrence Handle10067836 Occurrence Handle1:CAS:528:DyaK1MXhsFCjt7c%3D C. G. Östenson V. Grill (1986) Mol. Cell. Endocrinol. 45 IssueID2–3 215–221 Occurrence Handle3086158 K. Rezaei K. Saar U. Soomets A. Valkna J. Näsman M. Zorko K. Åkerman T. Schroeder T. Bartfai Ü. Langel (2000) Neuropeptides 34 IssueID1 25–31 Occurrence Handle10.1054/npep.1999.0782 Occurrence Handle10688965 Occurrence Handle1:CAS:528:DC%2BD3cXit1egt7o%3D T. Sano K. Ohyama Y. Yamano Y. Nakagomi S. Nakazawa M. Kikyo H. Shirai J. S. Blank J. H. Exton T. Inagami (1997) J. Biol. Chem. 272 IssueID38 23631–23636 Occurrence Handle10.1074/jbc.272.38.23631 Occurrence Handle9295303 Occurrence Handle1:CAS:528:DyaK2sXmtlOit7w%3D I. Shimizu M. Hirota C. Ohboshi K. Shima (1987) Endocrinology 121 IssueID3 1076–1082 Occurrence Handle3040376 Occurrence Handle1:CAS:528:DyaL2sXlt1Olur4%3D Occurrence Handle10.1210/endo-121-3-1076 H. Shirai K. Takahashi T. Katada T. Inagami (1995) Hypertension 25 IssueID4 Pt 2 726–730 Occurrence Handle7721423 Occurrence Handle1:CAS:528:DyaK2MXlvVemsbs%3D S. Takhar S. Gyomorey R. C. Su S. K. Mathi X. Li M. B. Wheeler (1996) Endocrinology 137 IssueID5 2175–2178 Occurrence Handle10.1210/en.137.5.2175 Occurrence Handle8612565 Occurrence Handle1:CAS:528:DyaK28XisFCqt78%3D H. Tang D. F. Guo J. P. Porter Y. Wanaka T. Inagami (1998) Circ. Res. 82 IssueID5 523–531 Occurrence Handle9529156 Occurrence Handle1:CAS:528:DyaK1cXitVSktLg%3D J. B. Thompson S. M. Wade J. K. Harrison M. N. Salafranca R. R. Neubig (1998) J. Pharmacol. Exp. Ther. 285 IssueID1 216–222 Occurrence Handle9536013 Occurrence Handle1:CAS:528:DyaK1cXisVCqsrY%3D R. M. Touyz C. Berry (2002) Braz. J. Med. Biol. Res. 35 IssueID9 1001–1015 Occurrence Handle10.1590/S0100-879X2002000900001 Occurrence Handle12219172 Occurrence Handle1:CAS:528:DC%2BD3sXmvVWhsA%3D%3D L. O. Uttenthal A. Toledano E. Blazquez (1992) Neuropeptides 21 IssueID3 143–146 Occurrence Handle10.1016/0143-4179(92)90036-V Occurrence Handle1352862 Occurrence Handle1:CAS:528:DyaK38XitVyiurg%3D Y. Wei S. Mojsov (1995) FEBS Lett. 358 IssueID3 219–224 Occurrence Handle10.1016/0014-5793(94)01430-9 Occurrence Handle7843404 Occurrence Handle1:CAS:528:DyaK2MXjsFamsro%3D M. B. Wheeler M. Lu J. S. Dillon X. H. Leng C. Chen A. E. Boyd Suffix3rd (1993) Endocrinology 133 IssueID1 57–62 Occurrence Handle10.1210/en.133.1.57 Occurrence Handle8391428 Occurrence Handle1:CAS:528:DyaK3sXlsFamsro%3D C. Widmann E. Burki W. Dolci B. Thorens (1994) Mol. Pharmacol. 45 IssueID5 1029–1035 Occurrence Handle8190093 Occurrence Handle1:CAS:528:DyaK2cXktVWmsLo%3D D. I. Yule J. A. Williams (1992) J. Biol. Chem. 267 IssueID20 13830–13835 Occurrence Handle1629184 Occurrence Handle1:CAS:528:DyaK38XltVCksb0%3D M. Zorko Ü. Langel (2005) Adv. Drug Deliv. Rev. 57 IssueID4 529–545 Occurrence Handle10.1016/j.addr.2004.10.010 Occurrence Handle15722162 Occurrence Handle1:CAS:528:DC%2BD2MXhslWgu7Y%3D