Synaptotagmin (Syt) constitutes a large family of putative membrane trafficking proteins that share a short extracellular domain, a single N-terminal transmembrane domain, and C-terminal tandem C2 domains. In this study, I identified and characterized a novel member of the Syt family (named Syt XV-a) in the mouse, the rat, and humans. Although Syt XV-a protein has a short hydrophobic region at the very end of the N terminus (i.e., lacks a putative extracellular domain), biochemical and cellular analyses have indicated that the short hydrophobic region (amino acids 5-22) is sufficient for producing type I membrane topology in cultured cells, the same as in other Syt family proteins. Unlike other Syt isoforms, however, the mouse and human Syt XV have an alternative splicing isoform that lacks the C-terminal portion of the C2B domain (named Syt XV-b). Since the expression of Syt XV-a/b mRNA was mainly found in non-neuronal tissues (e.g., lung and testis) and Syt XV-a C2 domains lack Ca2+-dependent phospholipid binding activity, Syt XV-a is classified as a non-neuronal, Ca2+-independent Syt. (C) 2003 Elsevier Science (USA). All rights reserved.