Convergent, RIC-8-Dependent Gα Signaling Pathways in the Caenorhabditis elegans Synaptic Signaling Network

We used gain-of-function and null synaptic signaling network mutants to investigate the relationship of the G alpha sub(q) and G alpha sub(s) pathways to synaptic vesicle priming and to each other. Genetic epistasis studies using G alpha sub(q) gain-of-function and null mutations, along with a mutation that blocks synaptic vesicle priming and the synaptic vesicle priming stimulator phorbol ester, suggest that the G alpha sub(q) pathway generates the core, obligatory signals for synaptic vesicle priming. In contrast, the G alpha sub(s) pathway is not required for the core priming function, because steady-state levels of neurotransmitter release are not significantly altered in animals lacking a neuronal G alpha sub(s) pathway, even though these animals are strongly paralyzed as a result of functional (nondevelopmental) defects. However, our genetic analysis indicates that these two functionally distinct pathways converge and that they do so downstream of DAG production. Further linking the two pathways, our epistasis analysis of a ric-8 null mutant suggests that RIC-8 (a receptor-independent G alpha guanine nucleotide exchange factor) is required to maintain both the G alpha sub(q) vesicle priming pathway and the neuronal G alpha sub(s) pathway in a functional state. We propose that the neuronal G alpha sub(s) pathway transduces critical positional information onto the core G alpha sub(q) pathway to stabilize the priming of selected synapses that are optimal for locomotion.