My laboratory is developing a body of information about the structure and function of bioactive proteins (toxins) in the venom of American scorpions. Scorpions cause significant threats to the public health in most of Latin America. 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 utilizes the interaction of laboratories in Mexico and Brazil. 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 has provided the basis for an approach to understanding pancreatitis and 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 that is initiated at the endoplasmic reticulum. There is mounting evidence of effects that target additional cellular compartments including the nucleus and mitochondria. 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 characterization of novel scorpion venom protein toxins. Knowledge of pancreatic functions as affected by these protein toxins is revealing information about the molecular basis for onset of acute pancreatitis and possibly pancreatic cancer. High performance computational support from the North Carolina Supercomputing Center (NCSC) has been vital for our studies of these bioactive venom proteins. We are currently embarked upon modeling, molecular dynamics, and NMR structural determination of these proteins. Image analysis from light and electron microscopic data of subcellular anatomical changes associated with both normal and disease processes will be reconstructed via massively parallel computational resources. By combining strengths in studies of both venom proteins and subcellular structure with protein export mechanisms we have been able to advance unique knowledge for investigating function of pancreatic acinar cells and their exocrine discharge. Our approach has resulted in 30 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.

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.

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.

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.

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." J. Biochem. 313:753-760.

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.