Dopamine signaling depends on rapid removal of dopamine from the synapse by the dopamine transporter (DAT), making DAT regulation critical for normal neurotransmission and drug responses. This study examined whether activation of the arachidonic acid (AA) signaling pathway regulates DAT function and trafficking. Using human embryonic kidney (HEK‑293) cells expressing human DAT and dopamine D2 receptors, we investigated the effects of the purported phospholipase A2 activator melittin. Melittin inhibited DAT function, directly interacted with the transporter, and promoted DAT internalization into early endosomes, followed by recycling back to the cell membrane. These results indicate that melittin regulates DAT through direct membrane interactions rather than specific activation of AA signaling pathways.
