Non-competitive metabotropic glutamate 1 receptor antagonists block activity of slowly adapting type I mechanoreceptor units in the rat sinus hair follicle.
Previous studies suggested that Group I metabotropic glutamate (mGlu) receptors play a role in mechanotransduction processes of slowly adapting type I mechanoreceptors. Using an isolated rat sinus hair follicle preparation we tested a range of compounds. Surprisingly, only non-competitive mGlu1 receptor antagonists produced profound and long-lasting depression of mechanically evoked firing. 6-Amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (YM-298198) had an IC(50) of 8.7 muM (95% CI 5.7 to 13.2 microM), representing the most potent known blocker of type I mechanoreceptors. The derivative 6-amino-N-cyclohexyl-3-methylthiazolo[3,2-alpha]benzimidazole-2-carboxamide hydrochloride (desmethyl YM-298198) had a comparable potency. Another compound 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) had a similar depressant effect, although it was less potent with an approximate IC(50) of 100 microM. Between three and seven times the concentration of CPCCOEt and YM-298198 respectively was required to produce similar depressions in slowly adapting type II units. No depression, and some weak excitatory effects, were observed using the following ligands: the competitive mGlu1 receptor antagonist alpha-amino-5-carboxy-3-methyl-2-thiopheneacetic acid (3-MATIDA) (300 microM), the phosphoserine phosphatase inhibitor dl-2-amino-3-phosphonopropionic acid (dl-AP3) (2 mM), non-competitive mGlu5 receptor antagonists 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; (S)-3,5-DHPG, (S)-3,5-dihydroxyphenylglycine (MTEP) (10 microM) and 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) (100 microM), the mGlu1 receptor agonist (S)-3,5-dihydroxyphenylglycine ((S)-3,5-DHPG) (500 microM), and the mGlu5 receptor agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) (1 mM). The results suggest that the non-competitive mGlu1 receptor antagonists are not acting at conventional mGlu1 receptors but at other binding sites, possibly those directly associated with mechanogated channels or on any of a number of indirect biochemical pathways. YM-298198 and related compounds may prove to be useful ligands to identify mechanosensitive channel proteins. The selective interference of type I units may provide further evidence that Merkel cells are mechanotransducers. Finally such compounds may deliver insights or treatments for Merkel cell carcinoma.
Cahusac
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PM
Department of Psychology, University of Stirling, Stirling FK9 4LA, Scotland. p.m.b.cahusac@stir.ac.uk
Mavulati
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SC
D000200:Action Potentials; D000818:Animals; D018859:Hair Follicle / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D040542:Mechanotransduction, Cellular; D018862:Merkel Cells / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors*
D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1