Mutations of TRPM8 channels: Unraveling the molecular basis of activation by cold and ligands.

"cylinders indicated ?-helices based on the secondary structure analysis of the different structures deposited in the protein data bank [color figure can be viewed at wileyonlinelibrary com ] table 1 summary of trpm8 mutations chimeric constructs and deletions and their effect upon cold and ligand stimuli mutation/chimeras/deletions stimuli/ptm effect on the mutant channel species references s9a icilin insensitive hs trpm8 [ ] phosphorylation impaired phosphorylation hs trpm8 [ ] t17a icilin insensitive hs trpm8 [ ] phosphorylation impaired phosphorylation hs trpm8 [ ] s26d cold/menthol wt phenotype mm trpm8 [ ] s26p cold/menthol hypersensitive phenotype mm trpm8 [ ] s26v cold/menthol wt phenotype mm trpm8 [ ] s27a cold/menthol wt phenotype mm trpm8 [ ] s27d cold/menthol wt phenotype mm trpm8 [ ] s27p cold/menthol hypersensitive phenotype mm trpm8 [ ] s29a cold/menthol enhanced response mm trpm8 [ ] r30q menthol enhanced response hs trpm8 [ ] g150r ws-12 undetectable response hs trpm8 [ ] k423n ws-12 reduced responses hs trpm8 [ ] r475c ws-12 reduced responses hs trpm8 [ ] r485w ws-12 undetectable response hs trpm8 [ ] y516e ws-12 undetectable response hs trpm8 [ ] w682a menthol no response rntrpm8 [ ] y745a menthol insensitive mm trpm8 [ ] icilin/cooling agent 10 insensitive hs trpm8 [ ] y745f menthol reduced potency mm trpm8 [ ] y745h cold wt responses mm trpm8 [ ] menthol insensitive no cold response potentiation mm trpm8 [ ] menthol no significant differences in binding hs trpm8-vsld [ ] menthol impaired binding hs trpm8 [ ] icilin insensitive no cold response potentiation mm trpm8 [ ] tacrolimus wt-like activation no cold responses potentiation mm trpm8 [ ] praziquantel no agonist activity reduced cold responses potentiation hs trpm8 [ ] bctc wt-like inhibitory responses mm trpm8 [ ] skf96365 no inhibition mm trpm8 [ ] capsazepine clotrimazole econazole reduced inhibition mm trpm8 [ ] pip 2 wt affinity mm trpm8 [ ] i746a icilin/cooling agent 10 reduced efficacy hs trpm8 [ ] naphthyl antagonist reduced inhibition hs trpm8 [ ] l774anap menthol anap peak emission redshifted mm trpm8 [ ] v791anap menthol anap peak emission redshifted mm trpm8 [ ] d796r cold/menthol sensitive hs trpm8 [ ] icilin no response attenuates response to menthol hs trpm8 [ ] glycosylation wt phenotype hs trpm8 [ ] q785a menthol dismissed desensitization pmtrpm8 [ ] n790a menthol dismished desensitization pmtrpm8 [ ] n799a cold/menthol sensitive rn trpm8 [ ] icilin insensitive maintaining cold responses potentiation rn trpm8 [ ] icilin insensitive hs trpm8 [ ] cooling agent 10 sensitive hs trpm8 [ ] tacrolimus wt phenotype mm trpm8 [ ] naphthyl antagonist enhanced potency hs trpm8 [ ] n799d cold/menthol reduced responses hs trpm8 [ ] icilin no response hs trpm8 [ ] glycosylation no matured n -glycosylated isoform hs trpm8 [ ] n799e icilin insensitive rn trpm8 [ ] n799y icilin insensitive rn trpm8 [ ] d802a cold/menthol sensitive rn trpm8 [ ] icilin insensitive hs trpm8 [ ] icilin insensitive no cold response potentiation rn trpm8 [ ] cooling agent 10 reduced potency hs trpm8 [ ] camphor wt phenotype hs trpm8 [ ] naphthyl antagonist reduced potency hs trpm8 [ ] d802e cold/menthol wt responses rn trpm8 [ ] icilin insensitive rn trpm8 [ ] d802h cold/menthol wt responses rn trpm8 [ ] icilin insensitive rn trpm8 [ ] d802k cold/menthol wt responses rn trpm8 [ ] icilin insensitive rn trpm8 [ ] d802n cold reduced responses hs trpm8 [ ] cold/menthol wt responses rn trpm8 [ ] cold/menthol sensitive hs trpm8 [ ] menthol increased current hs trpm8 [ ] icilin insensitive hs trpm8 [ ] icilin insensitive rn trpm8 [ ] glycosylation wt phenotype hs trpm8 [ ] d802q cold/menthol wt responses rn trpm8 [ ] icilin insensitive rn trpm8 [ ] d802r cold/menthol almost wt currents hs trpm8 [ ] icilin insensitive hs trpm8 [ ] glycosylation wt phenotype hs trpm8 [ ] d802s cold/menthol wt responses rn trpm8 [ ] icilin insensitive rn trpm8 [ ] d802y cold/menthol wt responses rn trpm8 [ ] icilin insensitive rn trpm8 [ ] a805 icilin insensitive naturally present in the avian trpm8 [ ] g805a cold/menthol wt responses rn trpm8 [ ] icilin insensitive no cold response potentiation rn trpm8 [ ] praziquantel wt responses hs trpm8 [ ] s824anap menthol anap emission redshifted mm trpm8 [ ] d835r any nonfunctional channel hs trpm8 [ ] glycosylation no matured n -glycosylated isoform hs trpm8 [ ] r842a cold reduced responses hs trpm8 [ ] menthol reduce response hs trpm8 [ ] r842d/e cold/menthol/icilin no response hs trpm8 [ ] glycosylation no matured n -glycosylated isoform hs trpm8 [ ] r842h menthol reduce response hs trpm8 [ ] menthol similar affinity as wt hs trpm8-vsld [ ] r842k menthol reduced responses hs trpm8 [ ] h844a menthol wt response fatrpm8 [ ] icilin strongly decrease response fatrpm8 [ ] h845a cold reduced responses hs trpm8 [ ] menthol wt responses hs trpm8 [ ] r851a any nonfunctional channel hs trpm8 [ ] r851q cold reduced responses hs trpm8 [ ] menthol wt responses hs trpm8 [ ] k856a cold hypersensitive phenotype hs trpm8 [ ] menthol enhanced sensitivity and affinity hs trpm8 [ ] k856r menthol wt responses hs trpm8 [ ] r862a cold reduced responses hs trpm8 [ ] menthol wt responses hs trpm8 [ ] a875anap menthol anap emission redshifted mm trpm8 [ ] r897e cold reduced responses mm trpm8 [ ] menthol wt responses mm trpm8 [ ] y905a cold/menthol/icilin nonfunctional trpm8 a [ ] y905f cold/menthol/icilin wt responses trpm8 a [ ] y905w cold/menthol/icilin strongly decreased current trpm8 a [ ] e906a cold/menthol/icilin inactive channel trpm8 a [ ] e906q cold/menthol/icilin reduced responses trpm8 a [ ] y908a/w cold/menthol strongly decreased current trpm8 a [ ] icilin wt responses trpm8 a [ ] y908f cold/menthol/icilin wt responses trpm8 a [ ] d918a/e/n cold/menthol/icilin wt responses trpm8 a [ ] y919v b cold increased current af trpm8 [ ] v919i cold/menthol/icilin wt responses trpm8 a [ ] v919y cold decreased current la trpm8 [ ] d920a/n cold/menthol/icilin drastic decrease in currents trpm8 a [ ] d920anap menthol anap emission redshifted mmtrpm8 [ ] t922anap menthol anap emission blueshifted mmtrpm8 [ ] g925i cold enhanced sensitivity la trpm8 [ ] g925q cold decreased sensitivity la trpm8 [ ] g925anap cold anap emission redshifted enhanced cold sensitivity la trpm8 [ ] c929a menthol/icilin/cold nonfunctional channel mm trpm8 [ ] n934d cold shifted threshold to lower temperature."

"This study was funded by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación and Fondo Europeo de Desarrollo Regional (MICIU/AEI/FEDER, UE), grant number RTI2018‐097189‐B‐C22 to R. G. M. and M. M. M., and CSIC grant numbers 201880E109 and 2019E030 to M. M. M. and R. G. M., respectively. A. P. C. thanks CSIC and IQM for a JAE Intro ICUs grant."