Academic journal article Genetics

Caenorhabditis Elegans TRPV Channels Function in a Modality-Specific Pathway to Regulate Response to Aberrant Sensory Signaling

Academic journal article Genetics

Caenorhabditis Elegans TRPV Channels Function in a Modality-Specific Pathway to Regulate Response to Aberrant Sensory Signaling

Article excerpt

ABSTRACT

Olfaction and some forms of taste (including bitter) are mediated by G protein-coupled signal transduction pathways. Olfactory and gustatory ligands bind to chemosensory G protein-coupled receptors (GPCRs) in specialized sensory cells to activate intracellular signal transduction cascades. G protein-coupled receptor kinases (GRKs) are negative regulators of signaling that specifically phosphorylate activated GPCRs to terminate signaling. Although loss of GRK function usually results in enhanced cellular signaling, Caenorhabditis elegans lacking GRK-2 function are not hypersensitive to chemosensory stimuli. Instead, grk-2 mutant animals do not chemotax toward attractive olfactory stimuli or avoid aversive tastes and smells. We show here that loss-of-function mutations in the transient receptor potential vanilloid (TRPV) channels OSM-9 and OCR-2 selectively restore grk-2 behavioral avoidance of bitter tastants, revealing modality-specific mechanisms for TRPV channel function in the regulation of C. elegans chemosensation. Additionally, a single amino acid point mutation in OCR-2 that disrupts TRPV channel-mediated gene expression, but does not decrease channel function in chemosensory primary signal transduction, also restores grk-2 bitter taste avoidance. Thus, loss of GRK-2 function may lead to changes in gene expression, via OSM-9/OCR-2, to selectively alter the levels of signaling components that transduce or regulate bitter taste responses. Our results suggest a novel mechanism and multiple modality-specific pathways that sensory cells employ in response to aberrant signal transduction.

TO survive, organisms must be able to recognize and respond appropriately to chemical cues in their environment that indicate the presence or absence of food, reproductive partners, or predators. Chemosensation is the fundamental process by which chemical signals, in the form of gustatory (taste) and olfactory (smell) stimuli, are detected. The sense of taste is particularly vital to ensure survival as it confers the ability to distinguish favorable food sources from hazardous compounds before they are ingested (Herness and Gilbertson 1999; Perez et al. 2003). Bitter or sour tastes usually indicate the presence of toxic compounds that would be rejected, whereas salty, sweet, and umami (amino acid) reflect the presence of valuable nutrients (Herness and Gilbertson 1999).

Olfaction and gustatory responses to bitter, sweet, and umami stimuli are generallymediated byGprotein-coupled signal transduction pathways that are conserved across species (Dryer and Berghard 1999; Chandrashekar et al. 2006; Palmer 2007). Signaling is initiated when a ligand (odorant or tastant) binds to a seven-transmembrane G protein-coupled receptor (GPCR), inducing a conformational change in the receptor that activates the associated heterotrimeric G proteins. The Ga subunit exchanges GDP for GTP and, now activated, dissociates from the Gβ and Gγ (Gβγ) subunits. Both the free Gα-GTP and Gβγ subunits can stimulate intracellular signaling cascades by interacting with downstream effectors such as adenylate cyclases, phospholipases, and ion channels (McCudden et al. 2005).

Following the activation of G protein-coupled signaling, a negative feedback mechanism known as desensitization is initiated (Hausdorff et al. 1990; Metaye et al. 2005). G protein-coupled receptor kinases (GRKs) recognize and phosphorylate activated GPCRs (Freedman and Lefkowitz 1996; Pitcher et al. 1998; Penn et al. 2000; Premont and Gainetdinov 2007). The phosphorylated GPCRs can then be bound by cytosolic arrestin proteins (Freedman and Lefkowitz 1996; Metaye et al. 2005; Premont and Gainetdinov 2007). GRK phosphorylation and arrestin binding result in the cessation ofGprotein signaling, even in the continued presence of agonist (Freedman and Lefkowitz 1996; Penn et al. 2000; Premont and Gainetdinov 2007). This desensitization process is necessary to avoid the potentially harmful effects that can result from excessive stimulation through activated GPCRs (Metaye et al. …

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