The TfX; Y) V7rearrangementin Drosophilahasoriginally been recognized as a SMe&ke mutant because of its behavioral and electrophysM@ cal phendype. The gene whose expression is altered by the V7 rearrangement has been characterized. It encodes a novel Ca*+-binding protein named frequenin, which is related to recoverin and visinin. In vitro, the frequenin protein functions like recoverin as a Ca*+-sensitive guanylyl cyclase activator. Anti-frequenin antibodies stain the central and peripheral nervous system in Drosophila embryos and in larval and adult tissue sections. Frequenin appears to be particularly enriched in synapses, such as the motor nerve endings at neuromuscular junctions. Neuromuscular junctions of transgenic flies, which overexpress frequenin upon heat shock, exhibit an extraordinarily enhanced, frequencydependent facilitation of neurotransmitter release, with properties identical to those observed in V7 junctions. We propose that frequenin represents a new element for the Ca2+ dependent modulation of synaptic efficacy.