Distinct functions of a cGMP-dependent protein kinase in nerve terminal growth and synaptic vesicle cycling

Abstract

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 FOR's exocytic and endocytic functions 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, where 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 signaling and this developmental effect was independent from FOR's effects on neurotransmission. Overall, FOR plays a critical role in coupling SV exocytosis and endocytosis, thereby balancing these two components to maintain sustained neurotransmission.