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Frog Skin Opioid Peptides

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Frog Skin Opioid Peptides . &............................................... Frog Skin Opioid Peptides: A Case for Naual ocring envirnntal substaces often mimic endogenous substances found in Environmental Mimicry mammals and are capable ofinteracting with *.specific.proteins, such as receptors, with a Lawrence H. Lazarus,' Sharon D. Bryant, MarttiAttila,2 and high degree of fidelity and selectivity. Severo Salvadori3 Narcotic aids and amphibian ski secre- introduced into human society 1Laboratory of Environmental Neuroscience, National Institute of Environmental Health tions, Sciences, Research Triangle Park, NC 27709 USA; 2Department of Pharmacy, University through close association with plants and of Helsinki, SF-00014 Helsinki, Finland; 3Department of Pharmaceutical Science, ;ials throughflk medicine and religious Italy divinatin prc':ices, were inicorporatedimto University of Ferrara, 1-44100 Ferrara, the armaientarium of thee early pharma- copoeia. These skin secretions contain a myriad of potent bioactive substances, Round the caldron go; (8), a well-known phenomenon amongst including aWkaoids, bioenic amines: pep- In thepoison 'd entrails throw. lepidopterans; for example, moths that take tids eny, mus, Ad toxins (n us on and pattern of the bark compounds roewithistaiding); each class Toad, that under coldstone, the coloration exhibits a broad range ofcharacteristic prop- Days and nights hast thirty-one on which they alight ("industrial melan- erties. nx cific group of peptides, the venom such contemporary case) and Swelter'd sleepinggot, ism" is one whopi..o g .h.ophins (drmal Boil thoufirst i'the charmedpot! the deliciously edible Viceroy butterfly that morphinelike substances)and t deltor- Macbeth (act IV, scene 1) adopts the wing pattern of the unpalatable phins (selectiveopioidx display remark- Monarch butterfly. Aposematism (same or able analgesic properties and include an Shakespeare's witches realized that potions a closely similar pattern shared by two or amino aidl with the rae (in a mammalian contained marvelous concoctions of ingre- more species) is encountered frequently cont H-ai i liu of the dorm dients (some obviously unattainable and throughout the animal kingdom, and sev- LCisomer. tsis of nrous stereospe- mythical in nature), several ofwhich could eral examples illustrate this phenomenon. cific analogues and conformational analyses of these peptide provided essential insights alone elicit the coveted effect. This cele- Among birds, three distinct species of into the tiar composition and microenvi- brated soliloquy reflects a unique knowl- African birds (the flycatcher, cuckoo- ronment of the rec pocket" nd' the edge of hereditary folklore that particular shrike, and tit) resemble the plumage of the opia Intdcin beOre reeporan lig- parts of animals and plants affect human aggressive drongos, while in New Guinea and that a biological response; new behavior (beliefs that continue in vogue several species ofpitohui and a female of an advances nt-he synthesis and receptor-bind- even as the twentieth century comes to a unrelated species (a bird of paradise) take zing proper-ti'sof the dtorphins are dis- close). In a sense, this witches' brew was a on the colored plumage of the hooded W edwin. h recip:tr-spyec.f opi- cocktail of unknown chemical composi- pitohui (5) which contains the toxic od pan mimics of tion that could mimic and interfere with homobatrachotoxin (a compound 500 endogenouss opoiods: their high selectivity for human pharmacological responses (ago- times more potent than strychnine!) (10). ether the p or receptor maks them formi- nists or antagonists that activate or block Tropical and neotropical amphibians exhibit dabke enyIronmentaildeivd agents in the pharmacological receptors leading to an abundance of mimicry in their striking addiction and in the treatment of wide changes at a physiological level, such as color combinations, many of which are variety of human disorders. Key words: stimulation or depression). Medicinal extremely poisonous (3). Reptilian mimicry pamphbias,. deltorpi morph evolu- chemistry is a recent outgrowth of our his- is also evident in the coloration and simi- tion, m imicry, moleculaW modeling, optate torical quest to define an active compo- larity of the banding patterns between the addiction, oMpep pt.ide .nthessy nent(s) from a host of biological sources- innocuous king snake and the deadly coral :Environ: eath Ppect102;:648-654 (1994) plants, invertebrates, and vertebrates alike snake. The semblance of an Australian sea- (1-5)-much like modern chemistry arose horse to its coral habitat affords protection from alchemy. from predators. Address correspondence to L. H. Lazarus, NIEHS, Environmental mimicry is a "copycat Mimicry also occurs in distinct ways in PO Box 12233, MD C3-04, Research Triangle evolved to other most notably among insects: Park, NC 27709 USA. theme" (6) whereby organisms species, S. Salvadori was supported by grants from CNR resemble something innocuous or poisonous the semblance of stick insects to dried Progetto Finalizzato Chimica Fine e Secondaria II as a defense against predation. Mimicry can twigs, moth larvae to dried leaves, and leaf and Murst. We are indebted to our Italian collabo- also be considered "adaptive convergence" insects to their habitat; some moths, bee- rators at both the University of Ferrara, Ferrara, among different species living under similar tles, and flies have even "copied" the phys- Italy, and P. A. Temussi, T. Tancredi, and their environmental conditions, such as adapta- ical appearance ofvarious species of preda- associates in the University ofNaples, Naples, Italy; A of in their bid to James E. Huff and Joseph T. Wachsman for tion ofoceanic vertebrates (past and present) tory wasps. variety plants, their suggestions during the preparation of this arti- with streamlined bodies and paddlelike for insect pollinators, mimic not only the cle, Joel Casey and Jack Field for their computer limbs or fins (7,8) and antigenic conver- reproductive apparatus of other nonrelat- expertise, Kenneth Jefferies for assistance in collect- gence among phylogenetically diverse para- ed species, but also physically resemble ing rat brains, Elizabeth West for her artistic talents sitic helminths in vertebrate hosts (9). In a insects (such as bees) to trick them into in preparing the figures, and the anonymous broader sense, mimicry includes coloration mating with the plant in order to cover reviewers for their critical evaluation of the manu- with Other in the script. We further and most gratefully appreciate (protective, obliterative, warning) and them pollen. plants, the invaluable librarians, in particular Ralph J. "protective resemblance," chemical resis- Judean desert for example, acquire the red Hester and Frances T. Lyndon, who provided us tance, and antigenic determinants (9). The color that attracts scarab beetles who, dur- with publications from obscure journals, innumer- classic example that we associate with envi- ing mating on the flower, carry away near- able articles, and current literature searches. ronmental mimicry is "MUllerian mimicry" ly 20 times more pollen than bees. Received 24 February 1994; accepted 23 May 1994. 648 Environmental Health Perspectives I_- - 9 This topic is not only fascinating to ATPase) (3); alkaloids (including the receptors are coming to the forefront in evolutionary biologists and ecologists, but major classes of dendrobatid alkaloids- research on human disease and animal also to biochemists, molecular biologists, batrachotoxins, histrionicotoxins, indolizi- biology.) Have not mammals evolved in and toxicologists (1). When examined at dines, pumiliotoxin-A, and decahydro- divergent directions for the past 230-255 the molecular level, mimicry illustrates an quinolines-and numerous minor classes- million years from their amphibian ances- even more bewildering diversity and bizarre gephyrotoxins, 2,6-disubstituted piperidines, tors or over an even greater time span from theme of adaptation to a microenviron- pyrrolidine alkaloids, pyridyl-piperidines, the experimental prototypes of life in the ment (6). The synthesis and secretion of a indole alkaloids, azatricyclododecenes, Cambrian and Proterozoic eras (two bil- bevy ofchemicals serve a variety ofpurposes: amidine alkaloids, epibatidine, saman- lion distant years past) that eventually gave attractants, for instance, in fungi or "fungal darine alkaloids, morphine, tetrodotoxins, way to our extant phyla? What could be pseudoflowers," which reproduce the taste and a group of miscellaneous piperidine- the basis for molecular mimicry or the sta- and odor of flowers to attract insects as based alkaloids), which collectively total bility of receptor recognition mechanisms vectors in their transmission (6); repellents, more than 200 compounds primarily from since the origin of protozoans, such as such as the toxic compounds associated toxic neotropic frogs of the genera Tetrahymena, which has opioid receptors with the monarch butterfly, hooded pitohui, Dendrobates and Phyi1obates (3); biogenic (19,20)? Could the protozoan 5 receptor and other organisms; camouflage, as beau- amines (consist of three distinct groups, type be the archaic progenitor for p and K tifully seen in the complete correspon- the indolealkylamines, imidazolealky- receptors based on the degree of sequence dence, synthesis, and chemical identity of lamines and phenylalkylamines, the latter similarity among them by evolving (21) larval hydrocarbons of the fly Microdon to of which includes common
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