Plasma membrane forms of guanylyl cyclase have been shown to function as natrluretlc peptide receptors. We describe a new clone (GCC) encoding a guanylyl cyclase receptor for heat-stable enterotoxln. GCC encodes a protein containing an extracellular amino acid sequence divergent from that of previously cloned guanylyl cyclases; however, the protein retains the intracellular protein kinasallke and cyclase catalytic domains. Expression of GC-C in COS-7 cells results in high guanylyl cyclase activity. In addition, heat-stable enterotoxin from E. coli, but not natrluretic peptldes, causes marked elevations of cyclic GMP and is specifically bound by cells transfected with GC-C. The enterotoxin falls to elevate cyclic GMP in nontransfected cells or in cells transfected with the natriuretlc peptidelguanylyl cyclase receptors. These results show that a heat-stable enterotoxin receptor responsible for acute diarrhea is a plasma membrane form of guanylyl cyclase.