Paul L. Fletcher, Jr.
Associate Professor Emeritus
BA,Virginia Polytechnic Institute & State University
MS, University of North Carolina at Greensboro
PhD, Vanderbilt University
My laboratory is developing a body of information about the structure and function of exocrine pancreatic secretory discharge; primarily when exposed to bioactive proteins (toxins) in the venom of American scorpions. Scorpions, especially those responsible for medically important adverse events in humans, are found on all continents in a broad band equatorially centered, but extending into subtropical regions. Scorpions cause significant threats to the public health in most of the world. Medical reports as early as 1938 associated scorpion stings in humans with immediate onset of acute pancreatitis. Our initial toxin isolations and characterizations were published with effects on pancreatic secretion. Information derived from our studies involved the interaction of laboratories in Latin America. Joint research is facilitating molecular taxonomy, characterization of the venom protein structure and function, and potential production of improved clinical antisera. Our research in pancreatic acinar cell function and the effects of scorpion toxins is revealing information about the molecular basis for onset of acute pancreatitis and possibly pancreatic cancer. Scorpion toxins active in pancreatic secretion include those that act on ion channels (Na+, K+, and Ca2+), G Protein coupled receptors (GPCR), and signaling kinases related to Protein Kinase C (PKC). Not only is secretory vesicle discharge directly affected, but also vesicular transport signaling, transport, and fusion events. This research is revealing previously unknown interactions and examines important connections between cellular and subcellular functions of the exocrine pancreas. These studies are paralleled by isolation and chemical characterization of novel scorpion venom protein toxins. We recently described the structure and function of Antarease, a novel metalloprotease similar in action to the clostridial neurotoxins, which cleaves SNARE proteins important in controlling the transport and fusion of intracellular vesicular traffic. High performance computational support from the ECU Center for Applied Computational Studies has been vital for our studies of these bioactive venom proteins. We are currently embarked upon modeling, molecular dynamics, and structure determination of these proteins. Image analysis from light and electron microscopic data of subcellular anatomical changes associated with both normal and disease processes provides unique insight. By combining studies of both venom proteins and subcellular structure of protein export mechanisms we have been able to advance fundamental knowledge for investigating exocrine discharge in pancreatic acinar cells. Our approach has resulted in nearly 40 publications and numerous presentations.
Possani, L.D., Martin, B.M., Fletcher, M.D., and Fletcher, P.L., Jr. 1991. “Discharge Effect on Pancreatic Exocrine Secretion Produced by Toxins Purified from Tityus serrulatus Scorpion Venom.” J. Biol. Chem.266(5):3178-3185. PMID:1993690
Fletcher, Jr., M.D. Fletcher, L.D. Possani. 1992. Characteristics of pancreatic exocrine secretion produced by venom from the Brazilian scorpion Tityus serrulatus. European Journal of Cell Biology. 58: 259-270. PMID:1385124
Possani, L.D., Fletcher, P.L., Jr., Fletcher, M.D., Rode, G.S., Mochca-Morales, J., Lucas, S., Coronas, F.V., Alagon, A.C., Martin, B.M. 1992. “Structural and Functional Characteristics of Toxins Purified from the Venom of the Brazilian Scorpion Tityus Serrulatus Lutz and Mello.” Memorias do Instituto Butantan, Sao Paulo, Brazil. 54,(2):25-52.
Valdivia, H.H., Martin, B.M., Fletcher, P.L., and Possani, L.D. 1994. “Isolation and Pharmacological Characterization of Four Novel Na+ Channel-Blocking Toxins from the Scorpion Centruroides noxius Hoffman.” J. Biochem. 116:1383-1391. PMID:7706233
Fletcher, M.D., Possani, L.D., Fletcher, P.L., Jr. 1994. “Morphological Studies by Light and Electron Microscopy of Pancreatic Acinar Cells Under the Effect of Tityus serrulatus Venom.” Cell and Tiss. Res.,278:255-264. PMID:8001082
Becerril, B., Corona, M., Coronas, F.I.V., Zamudio, T., Calderon-Aranda, E., Fletcher, Jr., P., Martin, B.M., and Possani, L.D. 1996. “Toxic Peptides and Genes Encoding Gamma Toxin of the Brazilian Scorpions Tityus bahiensis and Tityus stigmurus.” Biochem J. 313:753-760. PMID:8611151
Fletcher, P.L., Fletcher, M.D., Fainter, L.K., and Terrian, D.M. 1996. “Action of New World Scorpion Venom and its Neurotoxins in Secretion” Toxicon, 34(11/12):1399-1411. PMID:9027997
Holaday, S. K. Jr., Martin, B. M., Fletcher, P. L. Jr., and Krishna, N. R.; (2000); “NMR Structure of Butantoxin from the Scorpion, Tityus serrulatus” Archives of Biochemistry and Biophysics, 379:18-27. PMID:10864437
Fletcher, P.L., Jr. Fletcher, M.D., Weninger, K., Anderson, T.E., and Martin, B.M., (2009); “Vesicle-Associated Membrane Protein (VAMP) Cleavage by a New Metalloprotease from the Brazilian Scorpion Tityus serrulatus.” J. Biol. Chem., 285(10):74057416. PMID:20026600