An animal's ability to detect and avoid toxic compounds in the environment is crucial for survival. We show that the nematode Caenorhabditis elegans avoids many water-soluble substances that are toxic and that taste bitter to humans. We have used laser ablation and a genetic cell rescue strategy to identify sensory neurons involved in the avoidance of the bitter substance quinine, and found that ASH, a polymodal nociceptive neuron that senses many aversive stimuli, is the principal player in this response. Two G protein alpha subunits GPA-3 and ODR-3, expressed in ASH and in different, nonoverlapping sets of sensory neurons, are necessary for the response to quinine, although the effect of odr-3 can only be appreciated in the absence of gpa-3. We identified and cloned a new gene, qui-1, necessary for quinine and SDS avoidance. qui-1 codes for a novel protein with WD-40 domains and which is expressed in the avoidance sensory neurons ASH and ADL.

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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 small nematode Caenorhabditis elegans lives in the soil, where mechanical, thermal and most of all chemical stimuli strongly influence its behavior. Here we briefly review how chemical sensitivity is organized at the cellular and molecular level in this organism. C. elegans has less than 40 chemosensory neurons. With few exceptions each neuron senses more than one substance and each substance is sensed by more than one neuron. At the molecular level, as in other organisms, also in C. elegans, seven transmembrane G-protein-coupled receptors (GPCRs), heterotrimeric G proteins, cyclic nucleotidegated ion channels, TRP channels and Ca++ play crucial roles in chemical sensitivity. An unusual feature, possibly due to C. elegans's strong dependence on chemical cues, is the very large number of GPCR chemoreceptor genes (1300-1700) coded in its genome. Genetic approaches have also allowed the identification of new molecules involved in chemical sensitivity that would not have been discovered otherwise. In addition to the basic factors involved in primary signalling, the studies in C. elegans have revealed a network of regulatory pathways and molecules suggesting that fine modulation of the responsiveness of neurons is important, possibly to allow worms to negotiate a continuously changing environment. The experimental versatility of C. elegans has made it possible, in many cases, to determine precisely in which neuron a given molecule or pathway is required and for which biological response. This type of information can contribute to the general field of sensory signalling because it provides correlations between the biochemical properties of molecules and their cellular functions and between these and the in vivo behavioral responses of the animal.

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