Decoupling of Axonal Targeting and Behavioral Function in the Drosophila melanogaster Sex Peptide Receptor

ABSTRACT The Sex Peptide Receptor (SPR), a G‐protein coupled receptor (GPCR), is essential for mediating post‐mating behavioral responses in Drosophila melanogaster females. While SPR is known to be localized to axons, the molecular mechanisms driving this process and its functional necessity for behavior have been unclear. Here, we demonstrate that the N‐terminal domain of SPR is necessary for its axonal targeting in both Drosophila ventral nerve cord neurons and mouse hippocampal neurons. We mapped this targeting function to a critical region (amino acids 41−80) containing a conserved tyrosine‐based sorting motif (YGNE). Structural modeling predicts a potential interaction between this region and the m3A subunit of the AP‐3 adaptor complex, indicating a potential mechanism for AP‐3 mediated trafficking. We report a striking functional decoupling between receptor localization and behavioral output. The N‐terminal domain, and therefore axonal localization, was found to be dispensable for SPR's primary role in regulating female remating behavior. Conversely, the C‐terminal domain, while less critical for axonal targeting than the N‐terminus, proved essential for this behavioral function. These findings provide a new mechanistic insight into SPR sorting and reveal that signaling from non‐axonal compartments is sufficient to control this key reproductive behavior.