Cycloheximide: No ordinary bitter stimulus

Abstract

Cycloheximide (CyX), a toxic antibiotic with a unique chemical structure generated by the actinomycete, Streptomyces griseus, has emerged as a primary focus of studies on mammalian bitter taste. Rats and mice avoid it at concentrations well below the thresholds for most bitter stimuli and T2R G-protein-coupled receptors specific for CyX with appropriate sensitivity are identified for those species. Like mouse and rat, golden hamsters, Mesocricetus auratus, also detected and rejected micromolar levels of CyX, although 1mM CyX failed to activate the hamster chorda tympani nerve. Hamsters showed an initial tolerance for 500microM CyX, but after that, avoidance of CyX dramatically increased, plasticity not reported for rat or mouse. As the hamster lineage branches well before division of the mouse-rat lineage in evolutionary time, differences between hamster and mouse-rat reactions to CyX are not surprising. Furthermore, unlike hamster LiCl-induced learned aversions, the induced CyX aversion neither specifically nor robustly generalized to other non-ionic bitter stimuli; and unlike adverse reactions to other chemosensory stimuli, aversions to CyX were not mollified by adding a sweetener. Thus, CyX is unlike other bitter stimuli. The gene for the high-affinity CyX receptor is a member of a cluster of five orthologous T2R genes that are likely rodent-specific; this "CyX clade" is found in the mouse, rat and probably hamster, but not in the human or rabbit genome. The rodent CyX-T2R interaction may be one of multiple lineage-specific stimulus-receptor interactions reflecting a response to a particular environmental toxin. The combination of T2R multiplicity, species divergence and gene duplication results in diverse ligands for multiple species-specific T2R receptors, which confounds definition of 'bitter' stimuli across species.

Bitter triggers acetylcholine release from polymodal urethral chemosensory cells and bladder reflexes

“…In contrast, on other mucosal surfaces, such as the urethral lining, these qualities represent potentially harmful (aversive) content. Bacteria produce and secrete bitter receptor-activating substances (5,37,38). In biofilms, such substances from the Gram-negative bacterium Pseudomonas aeruginosa, one of the predominant causative microorganisms in catheter-associated urinary tract infection (39), can reach concentrations as high as 600 μM (40).…”

Cracking taste codes by tapping into sensory neuron impulse traffic

“…As noted above (cf., section 3), GL activation may assist behavioral discriminations between acids and ionic bitter stimuli made by rats via activation of GG acid-generalists and quinine-generalists (Breza et al ., 2007). However, the aversive non-ionic bitter stimuli caffeine and sucrose octaacetate (SOA) fail to activate the hamster CT (Frank et al ., 2004) and threshold CT activation by non-ionic cycloheximide is more than 10,000 times higher than the hamster aversion threshold (Hettinger et al ., 2007). …”

“…According to Shi and Zhang (2006), T1R sweet receptors evolved more slowly than T2R, the candidate GPCR bitter receptors (cf., below); still, species variation in T1R structure approaches the variability associated with lineage-specific “environmental response” enzymes (Berenbaum, 2002; Hettinger et al ., 2007). Evolution equips sweet receptors with sufficient flexibility to accommodate the energy needs in the diverse habitats of many different species.…”

“…8; Boughter et al ., 2005; Frank et al . 2004; Hettinger et al ., 2007; Hisatsune et al ., 2007), which are more effective when applied to posterior oral regions within receptive fields of the glossopharngeal nerve (Geran and Travers, 2006). …”

“…The especially great species diversity for high-affinity “bitter” tastes (Hettinger et al ., 2007) reflects an extremely rapid T2R evolution (Shi et al ., 2003; Shi and Zhang, 2006; Chandrashekar et al ., 2006). For example, humans are 100,000 times more sensitive to ionic denatonium and hamsters are 3000 times more sensitive to non-ionic cycloheximide.…”