Abstractα‐latrotoxin (α‐LTX) binds to several cell surface receptors including receptor protein‐tyrosine phosphatase σ (RPTPσ). Here we demonstrate that transient overexpression of the short splice variant 3 conferred α‐LTX induced secretion to hamster insulinoma (HIT‐15) cells. In contrast, the long splice variant 2 containing four additional extracellular fibronectin‐III domains was inactive in secretion or in a single cell assay. Toxin‐sensitive (MIN6) and toxin‐insensitive (HIT‐T15) insulinoma cell lines as well as PC12 cells expressed similar amounts of endogenous short RPTPσ splice variant suggesting that this receptor does not play a role for toxin‐sensitivity. J. Cell. Biochem. © 2006 Wiley‐Liss, Inc.