Tissue-specific alternative splicing generates two synaptojanin isoforms with differential membrane binding properties

Synaptojanin is an Src homology 3 domain-binding inositol 5-phosphatase that is thought to function in synaptic vesicle endocytosis. It is encoded by a cDNA with two open reading frames separated by an in-frame stop codon. The first open reading frame encodes a 145-kDa form of the protein, whereas a 170-kDa isoform appears to be composed of both open reading frames and contains additional Src homology 3 domain-binding consensus sequences. Here, we demonstrate that the two synaptojanin isoforms are generated by the alternative use of an exon containing the stop codon. Whereas the 145-kDa isoform is highly enriched in adult brain, the 170-kDa isoform is excluded from this tissue and has a widespread distribution in non-neuronal cells. Unlike the 145-kDa isoform, which can be removed from membranes by a low salt wash, the 170-kDa isoform remains membrane-associated, even in the presence of 1 M salt. Further, the 170-kDa form, but not the 145-kDa form, can be isolated from membranes as part of a large molecular weight complex. These properties may allow the 170-kDa isoform of synaptojanin to play a unique and perhaps more general role in endocytosis as compared with the 145-kDa isoform.