title: Abscisic Acid Acts as a Blocker of the Bitter Taste G Protein-Coupled Receptor T2R4.
abstract: Bitter taste receptors (T2Rs) belong to the G protein-coupled receptor superfamily. In humans, 25 T2Rs mediate bitter taste sensation. In addition to the oral cavity, T2Rs are expressed in many extraoral tissues, including the central nervous system, respiratory system, and reproductive system. To understand the mechanistic roles of the T2Rs in oral and extraoral tissues, novel blockers or antagonists are urgently needed. Recently, we elucidated the binding pocket of T2R4 for its agonist quinine, and an antagonist and inhibitory neurotransmitter, γ-aminobutyric acid. This structure-function information about T2R4 led us to screen the plant hormone abscisic acid (ABA), its precursor (xanthoxin), and catabolite phaseic acid for their ability to bind and activate or inhibit T2R4. Molecular docking studies followed by functional assays involving calcium imaging confirmed that ABA is an antagonist with an IC50 value of 34.4 ± 1.1 μM. However, ABA precursor xanthoxin acts as an agonist on T2R4. Interestingly, molecular model-guided site-directed mutagenesis suggests that the T2R4 residues involved in quinine binding are also predominantly involved in binding to the novel antagonist, ABA. The antagonist ability of ABA was tested using another T2R4 agonist, yohimbine. Our results suggest that ABA does not inhibit yohimbine-induced T2R4 activity. The discovery of natural bitter blockers has immense nutraceutical and physiological significance and will help in dissecting the T2R molecular pathways in various tissues.
authors.affiliation: †Department of Oral Biology, University of Manitoba, Winnipeg, MB R3E 0W4, Canada.
authors.forename: Sai P
authors.initials: SP
authors.lastname: Pydi
authors.affiliation: †Department of Oral Biology, University of Manitoba, Winnipeg, MB R3E 0W4, Canada.
authors.forename: Appalaraju
authors.initials: A
authors.lastname: Jaggupilli
authors.affiliation: ∥Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, SK S7N 5C9, Canada.
authors.forename: Ken M
authors.initials: KM
authors.lastname: Nelson
authors.affiliation: ∥Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, SK S7N 5C9, Canada.
authors.forename: Suzanne R
authors.initials: SR
authors.lastname: Abrams
authors.affiliation: †Department of Oral Biology, University of Manitoba, Winnipeg, MB R3E 0W4, Canada.
authors.forename: Rajinder P
authors.initials: RP
authors.lastname: Bhullar
authors.affiliation: ‡National Research Council of Canada, 110 Gymnasium Place, Saskatoon, SK S7N 0W9, Canada.|§Department of Biochemistry, University of Saskatchewan, 105 Wiggins Road, Saskatoon, SK S7N 5N5, Canada.
authors.forename: Michele C
authors.initials: MC
authors.lastname: Loewen
authors.affiliation: †Department of Oral Biology, University of Manitoba, Winnipeg, MB R3E 0W4, Canada.
authors.forename: Prashen
authors.initials: P
authors.lastname: Chelikani
mesh_terms: D000040:Abscisic Acid / Q000737:chemistry*; D001665:Binding Sites; D002338:Carotenoids / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry; D013329:Structure-Activity Relationship; D055697:Taste Perception / Q000502:physiology; D015016:Yohimbine / Q000737:chemistry; D000098706:Taste Receptors, Type 2
chemical_list: D043562:Receptors, G-Protein-Coupled; D012717:Sesquiterpenes; D000098706:Taste Receptors, Type 2; C012475:xanthoxin; D015016:Yohimbine; D002338:Carotenoids; D000040:Abscisic Acid