Latrophilin-1 is a brain-specific Orphan-B Receptor that binds alpha-latrotoxin, a potent presynaptic neurotoxin present in the venom of the black widow spider, in a Ca2+-independent manner. As with the other two latrophilins, it shares homology with lectin, olfactomedin, and transmembrane domains, and possesses variable C-termini and various alternative-splicing sites. CIRL is endogenously cleaved into two pieces at the GPCR proteolytic site (GPS) located adjacent to the first transmembrane helix as a mechanism to compartmentalize the cell adhesion and GPCR activation functions. Latrophilin-1 has been reported to be expressed predominantly in the brain. Very weak expression has also been documented in human heart, placenta, lung, liver, skeletal muscle, kidney, and pancreas. ESTs have been isolated from brain, eye, kidney, lung, and lymph node libraries. In addition, ESTs have been isolated from the following cancer libraries: brain, choriocarcinoma, epithelioid carcinoma, kidney, and lung.