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Originally published as Genetics Published Articles Ahead of Print on October 16, 2004.
Genetics, Vol. 169, 631-649, February 2005, Copyright © 2005
doi:10.1534/genetics.104.032334
Mutations That Rescue the Paralysis of Caenorhabditis elegans ric-8 (Synembryn) Mutants Activate the G
s Pathway and Define a Third Major Branch of the Synaptic Signaling Network
Michael A. Schade1, Nicole K. Reynolds1, Claudia M. Dollins2 and Kenneth G. Miller3
Program in Molecular, Cell and Developmental Biology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104
3 Corresponding author: Program in Molecular, Cell and Developmental Biology, Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK 73104.
E-mail: millerk{at}omrf.ouhsc.edu
To identify hypothesized missing components of the synaptic G
o-Gq signaling network, which tightly regulates neurotransmitter release, we undertook two large forward genetic screens in the model organism C. elegans and focused first on mutations that strongly rescue the paralysis of ric-8(md303) reduction-of-function mutants, previously shown to be defective in Gq pathway activation. Through high-resolution mapping followed by sequence analysis, we show that these mutations affect four genes. Two activate the Gq pathway through gain-of-function mutations in Gq; however, all of the remaining mutations activate components of the Gs pathway, including Gs, adenylyl cyclase, and protein kinase A. Pharmacological assays suggest that the Gs pathway-activating mutations increase steady-state neurotransmitter release, and the strongly impaired neurotransmitter release of ric-8(md303) mutants is rescued to greater than wild-type levels by the strongest Gs pathway activating mutations. Using transgene induction studies, we show that activating the Gs pathway in adult animals rapidly induces hyperactive locomotion and rapidly rescues the paralysis of the ric-8 mutant. Using cell-specific promoters we show that neuronal, but not muscle, Gs pathway activation is sufficient to rescue ric-8(md303)'s paralysis. Our results appear to link RIC-8 (synembryn) and a third major G pathway, the Gs pathway, with the previously discovered Go and Gq pathways of the synaptic signaling network.
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