Differential effects of bitter compounds on the taste transduction channels TRPM5 and IP3 receptor type 3.
Transient receptor potential cation channel subfamily M member 5 (TRPM5) is a Ca(2+)-activated nonselective cation channel involved in the transduction of sweet, bitter, and umami tastes. We previously showed that TRPM5 is a locus for the modulation of taste perception by temperature changes, and by quinine and quinidine, 2 bitter compounds that suppress gustatory responses. Here, we determined whether other bitter compounds known to modulate taste perception also affect TRPM5. We found that nicotine inhibits TRPM5 currents with an effective inhibitory concentration of ~1.3mM at -50 mV. This effect may contribute to the inhibitory effect of nicotine on gustatory responses in therapeutic and experimental settings, where nicotine is often employed at millimolar concentrations. In addition, it implies the existence of a TRPM5-independent pathway for the detection of nicotine bitterness. Nicotine seems to act from the extracellular side of the channel, reducing the maximal whole-cell conductance and inducing an acceleration of channel closure that leads to a negative shift of the activation curve. TRPM5 currents were unaffected by nicotine's metabolite cotinine, the intensive sweetener saccharin or by the bitter xanthines caffeine, theobromine, and theophylline. We also tested the effects of bitter compounds on another essential element of the sweet taste transduction pathway, the type 3 IP3 receptor (IP3R3). We found that IP3R3-mediated Ca(2+) flux is slightly enhanced by nicotine, not affected by saccharin, modestly inhibited by caffeine, theobromine, and theophylline, and strongly inhibited by quinine. Our results demonstrate that bitter compounds have differential effects on key elements of the sweet taste transduction pathway, suggesting for heterogeneous mechanisms of bitter-sweet taste interactions.
Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research, Herestraat 49, Campus Gasthuisberg, O&N1 Box 802, KU Leuven, B-3000 Leuven, Belgium. Karel.talavera@med.kuleuven.be.
Maarten
M
Gees
Yeranddy A
YA
Alpizar
Tomas
T
Luyten
Jan B
JB
Parys
Bernd
B
Nilius
Geert
G
Bultynck
Thomas
T
Voets
Karel
K
Talavera
D000818:Animals; D002118:Calcium / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009538:Nicotine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011802:Quinidine / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013549:Sweetening Agents / Q000494:pharmacology; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*
D053496:Inositol 1,4,5-Trisphosphate Receptors; D020033:Protein Isoforms; D013549:Sweetening Agents; D050053:TRPM Cation Channels; C498617:Trpm5 protein, mouse; D009538:Nicotine; D011803:Quinine; D011802:Quinidine; D002118:Calcium
caffeine; gustatory interaction; nicotine; quinine; sweet; taste mixture