Hiley, E.J.; (2006) G alpha 12 and rhogef mediated regulation of neurotransmission in Caenorhabditis elegans. Doctoral thesis , University of London.

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Abstract

The communication between neurons and other cells at chemical synapses, via the release of neurotransmitters, is a tightly regulated process. Regulation of the synaptic vesicle cycle, responsible for the release of neurotransmitters, controls the level of synaptic transmission. The identities of proteins involved in this regulation are gradually being elucidated using both in vitro and in vivo systems. In C. elegans adults the single Rho GTPase orthologue, RHO-1, stimulates neurotransmitter release at excitatory synapses at the neuromuscular junction. Expression of constitutively active RHO-1 increases release, whilst inhibition of endogenous RHO-1 by C3 transferase decreases release. RHO-1 stimulates release via two pathways, one that is dependent upon the diacylglycerol binding protein UNC-13 and the other that is independent of UNC-13. This thesis explores the upstream regulation of RHO-1. Data presented here suggests that one of the pathways acting upstream of RHO-1 in acetylcholine-releasing motor neurons depends upon Gcn2 (GPA-12), which acts via the single C. elegans RGS RhoGEF, (RHGF-1). Constitutively active GPA-12 has the same effect as constitutively active RHO-1, inducing the accumulation of diacylglycerol and the neuromodulator UNC-13 at release sites, and increased ACh release. All these effects are suppressed by mutation of RHGF-1. GPA-12 acts entirely in an UNC-13 dependent manner, suggesting the probability of other upstream pathways also stimulating RHO-1 to control neurotransmitter release.

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