The G Protein regulators EGL-10 and EAT-16, the Giα GOA-1 and the Gqα EGL-30 modulate the response of the C. elegansASH polymodal nociceptive sensory neurons to repellents

Abstract

BackgroundPolymodal, nociceptive sensory neurons are key cellular elements of the way animals sense aversive and painful stimuli. In Caenorhabditis elegans, the polymodal nociceptive ASH sensory neurons detect aversive stimuli and release glutamate to generate avoidance responses. They are thus useful models for the nociceptive neurons of mammals. While several molecules affecting signal generation and transduction in ASH have been identified, less is known about transmission of the signal from ASH to downstream neurons and about the molecules involved in its modulation.ResultsWe discovered that the regulator of G protein signalling (RGS) protein, EGL-10, is required for appropriate avoidance responses to noxious stimuli sensed by ASH. As it does for other behaviours in which it is also involved, egl-10 interacts genetically with the Go/iα protein GOA-1, the Gqα protein EGL-30 and the RGS EAT-16. Genetic, behavioural and Ca2+ imaging analyses of ASH neurons in live animals demonstrate that, within ASH, EGL-10 and GOA-1 act downstream of stimulus-evoked signal transduction and of the main transduction channel OSM-9. EGL-30 instead appears to act upstream by regulating Ca2+ transients in response to aversive stimuli. Analysis of the delay in the avoidance response, of the frequency of spontaneous inversions and of the genetic interaction with the diacylglycerol kinase gene, dgk-1, indicate that EGL-10 and GOA-1 do not affect signal transduction and neuronal depolarization in response to aversive stimuli but act in ASH to modulate downstream transmission of the signal.ConclusionsThe ASH polymodal nociceptive sensory neurons can be modulated not only in their capacity to detect stimuli but also in the efficiency with which they respond to them. The Gα and RGS molecules studied in this work are conserved in evolution and, for each of them, mammalian orthologs can be identified. The discovery of their role in the modulation of signal transduction and signal transmission of nociceptors may help us to understand how pain is generated and how its control can go astray (such as chronic pain) and may suggest new pain control therapies.

The C. elegans cGMP-Dependent Protein Kinase EGL-4 Regulates Nociceptive Behavioral Sensitivity

“…In response to quinine, a transient rise in intracellular calcium levels has been seen in the ASHs of wild-type animals [8], [17], [65]. We imaged quinine-evoked calcium fluxes in wild-type, egl-4(lof) and egl-4(gof) animals expressing G-CaMP3 in ASH ( sra-6p::G-CaMP3 ) [69], [70].…”

Structural Domains Required for Caenorhabditis elegans G Protein-coupled Receptor Kinase 2 (GRK-2) Function in Vivo

“…Although the C. elegans G␣ q/11 ortholog EGL-30 contributes to the modulation of ASH-mediated sensory signaling, the G␣ subunits ODR-3 and GPA-3, which are more similar to the G␣ i/o family, predominantly transduce ASH chemosensory signals (3,(42)(43)(44). We found that changing RH domain residues in Ce-GRK-2 that correspond to residues shown to mediate interaction between mammalian GRK2 and G␣ q/11 did not disrupt the ability of Ce-GRK-2 to restore ASH-mediated chemosensory behaviors (Fig.…”

“…The ASH sensory neurons rely mainly upon two stimulatory G␣s, ODR-3 and GPA-3, which are both most similar to the G␣ i/o family, to mediate aversion (3,(42)(43)(44)(45). EGL-30 is the single C. elegans G␣ q/11 ortholog, and it serves a modulatory role in aversive signaling (43).…”

“…EGL-30 is the single C. elegans G␣ q/11 ortholog, and it serves a modulatory role in aversive signaling (43). To determine whether the RH domain of Ce-GRK-2 mediates specific protein interactions that are necessary for its regulatory function in vivo, we introduced changes into Ce-GRK-2 (R106A, Y109I, and D110A) that correspond to mutations in the mammalian GRK2 RH domain that were previously shown to disrupt binding to G␣ q/11 (14).…”

AGS-3 AltersCaenorhabditis elegansBehavior after Food Deprivation via RIC-8 Activation of the Neural G Protein Gαo

“…The feeding state of the animal affects release of neurotransmitters that signal onto the ASHs to activate several G proteins that alter ASH function (Wragg et al, 2007; Harris et al, 2009; Harris et al, 2010; Ezak and Ferkey, 2010). Among these, Gα o acts by inhibiting glutamate release from ASHs (Harris et al, 2010; Esposito et al, 2010). We found that the AGS-3is expressed in ASH (Fig.…”