Bidirectional attack on the actin cytoskeleton. Bacterial protein toxins causing polymerization or depolymerization of actin

Toxicon

Volumn 60, Issue 4, 2012, Pages 572-581

  Aktories, Klaus ^a   Schwan, Carsten ^a   Papatheodorou, Panagiotis ^a   Lang, Alexander E ^a  

^a UNIVERSITY OF FREIBURG   (Germany)

Author keywords

Actin; ADP ribosylation; LSR; Microtubules; Photorhabdus luminescens; Toxins

Indexed keywords

ACTIN; ADENOSINE DIPHOSPHATE; ARGININE; BACTERIAL PROTEIN; BACTERIAL TOXIN; BOTULINUM TOXIN C 2; CLOSTRIDIUM DIFFICILE TRANSFERASE; CLOSTRIDIUM PERFRINGENS IOTA TOXIN; LIPOLYSIS STIMULATED LIPOPROTEIN RECEPTOR; LIPOPROTEIN RECEPTOR; PHOTORHABDUS LUMINESCENS TOXIN; THREONINE; UNCLASSIFIED DRUG;

ACTIN DEPOLYMERIZATION; ACTIN POLYMERIZATION; ADENOSINE DIPHOSPHATE RIBOSYLATION; CLOSTRIDIUM BOTULINUM; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM PERFRINGENS; CYTOSKELETON; HELA CELL; HUMAN; INSECT CELL; NONHUMAN; PHOTORHABDUS LUMINESCENS; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN FAMILY; PROTEIN MODIFICATION; REVIEW;

ACTIN CYTOSKELETON; ADP RIBOSE TRANSFERASES; ARGININE; BACTERIAL TOXINS; BOTULINUM TOXINS; CLOSTRIDIUM DIFFICILE; PHOTORHABDUS; POLYMERIZATION; PROTEIN CONFORMATION; TRANSFERASES;

BACTERIA (MICROORGANISMS); CLOSTRIDIUM BOTULINUM; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM PERFRINGENS; PHOTORHABDUS LUMINESCENS;

EID: 84863782095     PISSN: 00410101     EISSN: 18793150     Source Type: Journal    
DOI: 10.1016/j.toxicon.2012.04.338     Document Type: Review

References (107)

1. Acuto O., Cantrell D. T cell activation and the cytoskeleton. Annu. Rev. Immunol. 2000, 18:165-184.
2. Akhmanova A., Steinmetz M.O. Tracking the ends: a dynamic protein network controls the fate of microtubule tips. Nat. Rev. Mol. Cell Biol. 2008, 9:309-322.
3. Aktories K. Bacterial protein toxins that modify host regulatory GTPases. Nat. Rev. Microbiol. 2011, 9:487-498.
4. Aktories K., Barbieri J.T. Bacterial cytotoxins: targeting eukaryotic switches. Nat. Rev. Microbiol. 2005, 3:397-410.
5. Aktories K., Bärmann M., Ohishi I., Tsuyama S., Jakobs K.H., Habermann E. Botulinum C2 toxin ADP-ribosylates actin. Nature 1986, 322:390-392.
6. Aktories K., Just I., Rosenthal W. Different types of ADP-ribose protein bonds formed by botulinum C2 toxin, botulinum ADP-ribosyltransferase C3 and pertussis toxin. Biochem. Biophys. Res. Commun. 1988, 156:361-367.
7. Aktories K., Wegner A. ADP-ribosylation of actin by clostridial toxins. J. Cell Biol. 1989, 109:1385-1387.
8. Aktories K., Wegner A. Mechanisms of the cytopathic action of actin-ADP-ribosylating toxins. Mol. Microbiol. 1992, 6:2905-2908.
9. Aktories K., Weller U., Chhatwal G.S. Clostridium botulinum type C produces a novel ADP-ribosyltransferase distinct from botulinum C2 toxin. FEBS Lett. 1987, 212:109-113.
10. Barth H., Aktories K., Popoff M.R., Stiles B.G. Binary bacterial toxins: biochemistry, biology, and applications of common Clostridium and Bacillus proteins. Microbiol. Mol. Biol. Rev. 2004, 68:373-402.
11. Barth H., Blöcker D., Behlke J., Bergsma-Schutter W., Brisson A., Benz R., Aktories K. Cellular uptake of Clostridium botulinum C2 toxin requires oligomerization and acidification. J. Biol. Chem. 2000, 275:18704-18711.
12. Boquet P. Bacterial toxins inhibiting of activating small GTP-binding proteins. Ann. N.Y. Acad. Sci. 1999, 886:83-90.
13. Boquet P. Small GTP binding proteins and bacterial virulence. Microbes. Infect. 2000, 2:837-843.
14. Boquet P., Lemichez E. Bacterial virulence factors targeting Rho GTPases: parasitism or symbiosis?. Trends Cell Biol. 2003, 13:238-246.
15. Collier R.J. Membrane translocation by anthrax toxin. Mol. Aspects Med. 2009, 30:413-422.
16. Davies A.H., Roberts A.K., Shone C.C., Acharya K.R. Super toxins from a super bug: structure and function of Clostridium difficile toxins. Biochem. J. 2011, 436:517-526.
17. Desai A., Mitchison T.J. Microtubule polymerization dynamics. Annu. Rev. Cell Dev. Biol. 1997, 13:83-117.
18. Dmochewitz L., et al. Role of CypA and Hsp90 in membrane translocation mediated by anthrax protective antigen. Cell Microbiol. 2011, 13:359-373.
19. Dramsi S., Cossart P. Intracellular pathogens and the actin cytoskeleton. Annu. Rev. Cell Dev. Biol. 1998, 14:137-166.
20. Eckhardt M., Barth H., Blöcker D., Aktories K. Binding of Clostridium botulinum C2 toxin to asparagine-linked complex and hybrid carbohydrates. J. Biol. Chem. 2000, 275:2328-2334.
21. Ffrench-Constant R., Waterfield N. An ABC guide to the bacterial toxin complexes. Adv. Appl. Microbiol. 2006, 58:169-183.
22. Ffrench-Constant R., et al. Photorhabdus: towards a functional genomic analysis of a symbiont and pathogen. FEMS Microbiol. Rev. 2003, 26:433-456.
23. Fiorentini C., Falzano L., Travaglione S., Fabbri A. Hijacking Rho GTPases by protein toxins and apoptosis: molecular strategies of pathogenic bacteria. Cell Death Differ. 2003, 10:147-152.
24. Fritz G., Schroeder P., Aktories K. Isolation and characterization of a Clostridium botulinum C2 toxin-resistant cell line: evidence for possible involvement of the cellular C2II receptor in growth regulation. Infect. Immun. 1995, 63:2334-2340.
25. Galan J.E. Salmonella interactions with host cells: type III secretion at work. Annu. Rev. Cell Dev. Biol. 2001, 17:53-86.
26. Geipel U., Just I., Aktories K. Inhibition of cytochalasin D-stimulated G-actin ATPase by ADP-ribosylation with Clostridium perfringens iota toxin. Biochem. J. 1990, 266:335-339.
27. Geipel U., Just I., Schering B., Haas D., Aktories K. ADP-ribosylation of actin causes increase in the rate of ATP exchange and inhibition of ATP hydrolysis. Eur. J. Biochem. 1989, 179:229-232.
28. Gelfand V.I., Bershadsky A.D. Microtubule dynamics: mechanism, regulation, and function. Annu. Rev. Cell Biol. 1991, 7:93-116.
29. Genth H., Dreger S.C., Huelsenbeck J., Just I. Clostridium difficile toxins: more than mere inhibitors of Rho proteins. Int. J. Biochem. Cell Biol. 2008, 40:592-597.
30. Gordon V.M., Klimpel K.R., Arora N., Henderson M.A., Leppla S.H. Proteolytic activation of bacterial toxins by eukaryotic cells is performed by furin and by additional cellular proteases. Infect. Immun. 1995, 63:82-87.
31. Gruenheid S., Finlay B.B. Microbial pathogenesis and cytoskeletal function. Nature 2003, 422:775-781.
32. Gundersen G.G. Evolutionary conservation of microtubule-capture mechanisms. Nat. Rev. Mol. Cell Biol. 2002, 3:296-304.
33. Han S., Craig J.A., Putnam C.D., Carozzi N.B., Tainer J.A. Evolution and mechanism from structures of an ADP-ribosylating toxin and NAD complex. Nat. Struct. Biol. 1999, 6:932-936.
34. Hannappel E. Beta-thymosins. Ann. N.Y. Acad. Sci 2007, 1112:21-37.
35. Haug G., Aktories K., Barth H. The host cell chaperone Hsp90 is necessary for cytotoxic action of the binary iota-like toxins. Infect. Immun. 2004, 72:3066-3068.
36. Haug G., Leemhuis J., Tiemann D., Meyer D.K., Aktories K., Barth H. The host cell chaperone Hsp90 is essential for translocation of the binary Clostridium botulinum C2 toxin into the cytosol. J. Biol. Chem. 2003, 274:32266-32274.
37. Holmes K.C., Popp D., Gebhard W., Kabsch W. Atomic model of the actin filament. Nature 1990, 347:44-49.
38. Huff T., Muller C.S., Otto A.M., Netzker R., Hannappel E. Beta-thymosins, small acidic peptides with multiple functions. Int. J. Biochem. Cell Biol. 2001, 33:205-220.
39. Ireton K., Cossart P. Host-pathogen interactions during entry and actin-based movement of Listeria monocytogenes. Annu. Rev. Genet. 1997, 31:113-138.
40. Just I., Hennessey E.S., Drummond D.R., Aktories K., Sparrow J.C. ADP-ribosylation of Drosophila indirect flight muscle actin and arthrin by Clostridium botulinum C2 toxin and Clostridium perfringens iota toxin. Biochem. J. 1993, 291:409-412.
41. Kabsch W., Vandekerckhove J. Structure and function of actin. Annu. Rev. Biophys. Biophys. Chem. 1992, 21:49-76.
42. Kaiser E., Kroll C., Ernst K., Schwan C., Popoff M., Fischer G., Buchner J., Aktories K., Barth H. Membrane translocation of binary actin-ADP-ribosylating toxins from Clostridium difficile and Clostridium perfringens is facilitated by Cyclophilin A and Hsp90. Infect. Immun. 2011.
43. Kirschner M., Mitchison T. Beyond self-assembly: from microtubules to morphogenesis. Cell 1986, 45:329-342.
44. Kodama H., Baba T., Ohishi I. Inhibition of phagocytosis by rainbow trout (Oncorhynchus mykiss) macrophages by botulinum C2 toxin and its trypsinized component II. Dev. Comp. Immunol. 1994, 18:389-395.
45. Krantz B.A., Melnyk R.A., Zhang S., Juris S.J., Lacy D.B., Wu Z., Finkelstein A., Collier R.J. A phenylalanine clamp catalyzes protein translocation through the anthrax toxin pore. Science 2005, 309:777-781.
46. Landsberg M.J., Jones S.A., Rothnagel R., Busby J.N., Marshall S.D., Simpson R.M., Lott J.S., Hankamer B., Hurst M.R. 3D structure of the Yersinia entomophaga toxin complex and implications for insecticidal activity. Proc. Natl. Acad. Sci. U.S.A 2011, 108:20544-20549.
47. Lang A.E., Neumeyer T., Sun J., Collier R.J., Benz R., Aktories K. Amino acid residues involved in membrane insertion and pore formation of Clostridium botulinum C2 toxin. Biochemistry 2008, 47:8406-8413.
48. Lang A.E., Schmidt G., Schlosser A., Hey T.D., Larrinua I.M., Sheets J.J., Mannherz H.-G., Aktories K. Photorhabdus luminescens toxins ADP-ribosylate actin and RhoA to force actin clustering. Science 2010, 327:1139-1142.
49. Lansbergen G., Akhmanova A. Microtubule plus end: a hub of cellular activities. Traffic 2006, 7:499-507.
50. Lee S.C., et al. Structural characterisation of the insecticidal toxin XptA1, reveals a 1.15 MDa tetramer with a cage-like structure. J. Mol. Biol. 2007, 366:1558-1568.
51. Lemichez E., Lecuit M., Nassif X., Bourdoulous S. Breaking the wall: targeting of the endothelium by pathogenic bacteria. Nat. Rev. Microbiol. 2010, 8:93-104.
52. Lemonnier M., Landraud L., Lemichez E. Rho GTPase-activating bacterial toxins: from bacterial virulence regulation to eukaryotic cell biology. FEMS Microbiol. Rev. 2007, 31:515-534.
53. Li G., Rungger-Brändle E., Just I., Jonas J.-C., Aktories K., Wollheim C.B. Effect of disruption of actin filaments by Clostridium botulinum C2 toxin on insulin secretion in HIT-T15 cells and pancreatic islets. Mol. Biol. Cell 1994, 5:1199-1213.
54. Mannherz H.G., Hannappel E. The beta-thymosins: intracellular and extracellular activities of a versatile actin binding protein family. Cell Motil. Cytoskel. 2009, 66:839-851.
55. Masuda S., Oda Y., Sasaki H., Ikenouchi J., Higashi T., Akashi M., Nishi E., Furuse M. LSR defines cell corners for tricellular tight junction formation in epithelial cells. J. Cell Sci. 2011, 124:548-555.
56. Matter K., Dreyer F., Aktories K. Actin involvement in exocytosis from PC12 cells: studies on the influence of botulinum C2 toxin on stimulated noradrenaline release. J. Neurochem. 1989, 52:370-376.
57. Mauss S., Chaponnier C., Just I., Aktories K., Gabbiani G. ADP-ribosylation of actin isoforms by Clostridium botulinum C2 toxin and Clostridium perfringens iota toxin. Eur. J. Biochem. 1990, 194:237-241.
58. Mesli S., et al. Distribution of the lipolysis stimulated receptor in adult and embryonic murine tissues and lethality of LSR-/- embryos at 12.5 to 14.5 days of gestation. Eur. J. Biochem. 2004, 271:3103-3114.
59. Miller C.J., Elliott J.L., Collier R.J. Anthrax protective antigen: prepore-to-pore conversion. Biochemistry 1999, 38:10432-10441.
60. Norgauer J., Just I., Aktories K., Sklar L.A. Influence of botulinum C2 toxin on F-actin and N-formyl peptide receptor dynamics in human neutrophils. J. Cell Biol. 1989, 109:1133-1140.
61. - production and secretion but inhibits migration of activated human neutrophils. J. Clin. Invest. 1988, 82:1376-1382.
62. Ohishi I. Activation of botulinum C2 toxin by trypsin. Infect. Immun. 1987, 55:1461-1465.
63. Ohishi I. Structure and function of actin-adenosine-diphosphate-ribosylating toxins. Handbook of Experimental Pharmacology 2000, 253-273. Springer Verlag, Berlin. K. Aktories, I. Just (Eds.).
64. Ohishi I., Iwasaki M., Sakaguchi G. Purification and characterization of two components of botulinum C2 toxin. Infect. Immun. 1980, 30:668-673.
65. Ohishi I., Iwasaki M., Sakaguchi G. Vascular permeability activity of Botulinum C2 toxin elicited by cooperation of two dissimilar protein components. Infect. Immun. 1981, 31:890-895.
66. Ohishi I., Odagiri Y. Histopathological effect of botulinum C2 toxin on mouse intestines. Infect. Immun. 1984, 43:54-58.
67. Ohishi I., Tsuyama S. ADP-ribosylation of nonmuscle actin with component I of C2 toxin. Biochem. Biophys. Res. Commun. 1986, 136:802-806.
68. Papatheodorou P., Carette J.E., Bell G.W., Schwan C., Guttenberg G., Brummelkamp T.R., Aktories K. Lipolysis-stimulated lipoprotein receptor (LSR) is the host receptor for the binary toxin Clostridium difficile transferase (CDT). Proc. Natl. Acad. Sci. U.S.A 2011, 108:16422-16427.
69. Patel J.C., Galan J.E. Manipulation of the host actin cytoskeleton by Salmonella - all in the name of entry. Curr. Opin. Microbiol. 2005, 8:10-15.
70. Perelle S., Gibert M., Bourlioux P., Corthier G., Popoff M.R. Production of a complete binary toxin (actin-specific ADP-ribosyltransferase) by Clostridium difficile CD196. Infect. Immun. 1997, 65:1402-1407.
71. Perieteanu A.A., Visschedyk D.D., Merrill A.R., Dawson J.F. ADP-ribosylation of cross-linked actin generates barbed-end polymerization-deficient F-actin oligomers. Biochemistry 2010, 49:8944-8954.
72. Petosa C., Collier R.J., Klimpel K.R., Leppla S.H., Liddingtom R.C. Crystal structure of the anthrax toxin protective antigen. Nature 1997, 385:833-838.
73. Pirkl F., Buchner J. Functional analysis of the Hsp90-associated human peptidyl prolyl cis/trans isomerases FKBP51, FKBP52 and Cyp40. J. Mol. Biol. 2001, 308:795-806.
74. Pollard T.D. Actin. Curr. Opin. Cell Biol. 1990, 2:33-40.
75. Pollard T.D., Cooper J.A. Actin and actin-binding proteins. A critical evaluation of mechanisms and functions. Annu. Rev. Biochem. 1986, 55:987-1035.
76. Pollard T.D., Cooper J.A. Actin, a central player in cell shape and movement. Science 2009, 326:1208-1212.
77. Prepens U., Barth H., Wilting J., Aktories K. Influence of Clostridium botulinum C2 toxin on Fce{open}RI-mediated secretion and tyrosine phosphorylation in RBL cells. Naunyn-Schmiedeberg's Arch. Pharmacol. 1998, 357:323-330.
78. Pust S., Barth H., Sandvig K. Clostridium botulinum C2 toxin is internalized by clathrin- and Rho-dependent mechanisms. Cell Microbiol. 2010, 12:1809-1820.
79. Safer D., Nachmias V.T. Beta thymosins as actin binding peptides. Bioessays 1994, 16:473-479.
80. Schering B., Bärmann M., Chhatwal G.S., Geipel U., Aktories K. ADP-ribosylation of skeletal muscle and non- muscle actin by Clostridium perfringens iota toxin. Eur. J. Biochem. 1988, 171:225-229.
81. Schleberger C., Hochmann H., Barth H., Aktories K., Schulz G.E. Structure and action of the binary C2 toxin from Clostridium botulinum. J. Mol. Biol. 2006, 364:705-715.
82. Schmid G., Schürmann A., Huppertz C., Hofmann F., Aktories K., Joost H.-G. Inhibition of insulin-stimulated glucose transport in 3T3-L1 cells by Clostridium difficile toxin B, Clostridium sordellii lethal toxin, and Clostridium botulinum C2 toxin. Naunyn-Schmiedeberg's Arch. Pharmacol. 1998, 357:385-392.
83. Schnittler H.-J., Schneider S.W., Raifer H., Luo F., Dieterich P., Just I., Aktories K. Role of actin filaments in endothelial cell-cell adhesion and membrane stability under fluid shear stress. Pflügers Arch-Eur. J. Physiol. 2001, 442:675-687.
84. Schwan C., Noelke T., Kruppke A.S., Schubert D.M., Lang A.E., Aktories K. Cholesterol- and sphingolipid-rich microdomains are essential for microtubule-based membrane protrusions induced by Clostridium difficile transferase CDT. J. Biol. Chem. 2011.
85. Schwan C., Stecher B., Tzivelekidis T., van Ham M., Rohde M., Hardt W.D., Wehland J., Aktories K. Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS. Pathog. 2009, 5:e1000626.
86. Sheets J.J., Hey T.D., Fencil K.J., Burton S.L., Ni W., Lang A.E., Benz R., Aktories K. Insecticidal toxin complex proteins from Xenorhabdus nematophilus: structure and pore formation. J. Biol. Chem. 2011, 286:22742-22749.
87. Shupliakov O., Bloom O., Gustafsson J.S., Kjaerulff O., Low P., Tomilin N., Pieribone V.A., Greengard P., Brodin L. Impaired recycling of synaptic vesicles after acute perturbation of the presynaptic actin cytoskeleton. Proc. Natl. Acad. Sci. U.S.A 2002, 99:14476-14481.
88. Simpson L.L., Stiles B.G., Zepeda H., Wilkins T.D. Production by Clostridium spiroforme of an iotalike toxin that possesses mono(ADP-ribosyl)transferase activity: identification of a novel class of ADP-ribosyltransferases. Infect. Immun. 1989, 57:255-261.
89. Stiles B.G., Wilkens T.D. Purification and characterization of Clostridium perfringens iota toxin: dependence on two nonlinked proteins for biological activity. Infect. Immun. 1986, 54:683-688.
90. Sun J., Lang A.E., Aktories K., Collier R.J. Phenylalanine-427 of anthrax protective antigen functions in both pore formation and protein translocation. Proc. Natl. Acad. Sci. U.S.A 2008, 105:4346-4351.
91. Suttorp N., Polley M., Seybold J., Schnittler H., Seeger W., Grimminger F., Aktories K. Adenosine diphosphate-ribosylation of G-actin by botulinum C2 toxin increases endothelial permeability in vitro. J. Clin. Invest. 1991, 87:1575-1584.
92. Van T.M., Vandekerckhove J., Ampe C. Structural modules in actin-binding proteins: towards a new classification. Biochim. Biophys. Acta 1999, 1448:323-348.
93. Vandekerckhove J., Schering B., Bärmann M., Aktories K. Botulinum C2 toxin ADP-ribosylates cytoplasmic β/γ-actin in arginine 177. J. Biol. Chem. 1988, 263:696-700.
94. Visschedyk D.D., Perieteanu A.A., Turgeon Z.J., Fieldhouse R.J., Dawson J.F., Merrill A.R. Photox, a novel actin-targeting mono-ADP-ribosyltransferase from Photorhabdus luminescens. J. Biol. Chem. 2010, 285:13525-13534.
95. Waterfield N.R., Bowen D.J., Fetherston J.D., Perry R.D., Ffrench-Constant R.H. The Tc genes of Photorhabdus: a growing family. Trends Microbiol. 2001, 9:185-191.
96. Wegner A. Head tail polymerization of actin. J. Mol. Biol. 1976, 108:139-150.
97. Wegner A., Aktories K. ADP-ribosylated actin caps the barbed ends of actin filaments. J. Biol. Chem. 1988, 263:13739-13742.
98. Wegner A., Aktories K., Ditsch A., Just I., Schoepper B., Selve N., Wille M. Actin-gelsolin interaction. Adv. Exp. Med. Biol. 1994, 358:97-104.
99. Weigt C., Just I., Wegner A., Aktories K. Nonmuscle actin ADP-ribosylated by botulinum C2 toxin caps actin filaments. FEBS Lett. 1989, 246:181-184.
100. Welch M.D., Mallavarapu A., Rosenblatt J., Mitchison T.J. Actin dynamics in vivo. Curr. Opin. Cell Biol. 1997, 9:54-61.
101. Wex C.B.A., Koch G., Aktories K. Effects of Clostridium botulinum C2 toxin-induced depolymerisation of actin on degranulation of suspended and attached mast cells. Naunyn-Schmiedeberg's Arch. Pharmacol. 1997, 355:319-327.
102. Wiegers W., Just I., Müller H., Hellwig A., Traub P., Aktories K. Alteration of the cytoskeleton of mammalian cells cultured in vitro by Clostridium botulinum C2 toxin and C3 ADP-ribosyltransferase. Eur. J. Cell Biol. 1991, 54:237-245.
103. Wille M., Just I., Wegner A., Aktories K. ADP-ribosylation of the gelsolin-actin complex by clostridial toxins. J. Biol. Chem. 1992, 267:50-55.
104. Yen F.T., Masson M., Clossais-Besnard N., Andre P., Grosset J.M., Bougueleret L., Dumas J.B., Guerassimenko O., Bihain B.E. Molecular cloning of a lipolysis-stimulated remnant receptor expressed in the liver. J. Biol. Chem. 1999, 274:13390-13398.
105. Yen F.T., Roitel O., Bonnard L., Notet V., Pratte D., Stenger C., Magueur E., Bihain B.E. Lipolysis stimulated lipoprotein receptor: a novel molecular link between hyperlipidemia, weight gain, and atherosclerosis in mice. J. Biol. Chem. 2008, 283:25650-25659.
106. Young J.A., Collier R.J. Anthrax toxin: receptor binding, internalization, pore formation, and translocation. Annu. Rev. Biochem. 2007, 76:243-265.
107. Zepeda H., Considine R.V., Smith H.L., Sherwin J., Ohishi I., Simpson L.L. Actions of the Clostridium botulinum binary toxin on the structure and function of Y-1 adrenal cells. J. Pharmacol. Exp. Ther. 1988, 246:1183-1189.