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Sustained neurotransmission requires the tight coupling of synaptic vesicle (SV) exocytosis and endocytosis. The mechanisms underlying this coupling are poorly understood. We tested the hypothesis that a cGMP-dependent protein kinase (PKG), encoded by the foraging (for) gene in Drosophila melanogaster, is critical for this process using a for null mutant, genomic rescues and tissue-specific rescues. We uncoupled the exocytic and endocytic functions of FOR in neurotransmission using a temperature-sensitive shibire mutant in conjunction with fluorescein-assisted light inactivation of FOR. We discovered a dual role for presynaptic FOR, in which FOR inhibits SV exocytosis during low-frequency stimulation by negatively regulating presynaptic Ca2+ levels and maintains neurotransmission during high-frequency stimulation by facilitating SV endocytosis. Additionally, glial FOR negatively regulated nerve terminal growth through TGF-β signalling, and this developmental effect was independent of the effects of FOR on neurotransmission. Overall, FOR plays a critical role in coupling SV exocytosis and endocytosis, thereby balancing these two components to maintain sustained neurotransmission.

Original publication

DOI

10.1242/jcs.227165

Type

Journal article

Journal

J Cell Sci

Publication Date

05/04/2019

Volume

132

Keywords

Endocytosis, Exocytosis, Neurotransmitter release, Presynaptic, Synaptic transmission, Animals, Cyclic GMP-Dependent Protein Kinases, Drosophila Proteins, Drosophila melanogaster, Endocytosis, Exocytosis, Mutation, Neuromuscular Junction, Presynaptic Terminals, Signal Transduction, Synaptic Transmission, Synaptic Vesicles, Transforming Growth Factor beta