The mechanism by which Giardia lamblia exerts its pathogenicity is likely to be multifactorial. A 58 kDa enterotoxin was purified and characterized from the excretory-secretory product (ESP) of the parasite (Kaur et al. 2001). In the present study an attempt has been made to elucidate the mechanism of action of the ESP, a potentially important enterotoxin. A 41 kDa glycoprotein was identified in the mouse enterocyte membrane fraction with which the ESP interacted in a GM1-specific manner. The GTPase activity was reduced in enterocytes stimulated with the ESP, resulting in an increase in the level of adenylate cyclase-dependent cyclic adenosine monophosphate (cAMP). The activity of protein kinase A (PKA) in the enterocytes was also upregulated after ESP treatment. Ultimately, a significant increase in intracellular Ca2+ concentration and decrease in cytosolic Cl- level were noticed in ESP-stimulated mouse enterocytes. Thus it is possible that the enterotoxic ESP could bind to the 41 kDa glycoprotein (receptor?) on the enterocytes and activate the G-protein-mediated signal transduction pathway resulting in alteration of electrolyte transport.