ヒトTAS2R受容体ファミリーは、Family of G-protein-coupled receptors involved in human bitter taste detection。舌以外（気道・鼻副鼻腔・腸）にも発現し、味覚とは別の細胞自律的な化学検知に関与する（口外機能の生理的リガンドと発現検出法には争いがある）。
Verbatim: 'we use a heterologous expression system to show that specific T2Rs function as bitter taste receptors.' マウス T2R（mT2R-5）はシクロヘキシミドに応答し、ヒト hT2R-4 とマウス mT2R-8 はデナトニウムと 6-n-propyl-2-thiouracil に応答する。シクロヘキシミドへの感受性が低いマウス系統は mT2R-5 に受容体応答性を下げるアミノ酸置換を持ち、味物質依存的なガストデューシン活性化が実証された。TAS2R/T2R 受容体が苦味を媒介するという、Meyerhof グループから独立した機能的・遺伝学的証拠。
限界: 受容体レベルとマウス遺伝学の証拠。ヒト知覚への連結は in vitro で hT2R-4 が PROP/デナトニウムに応答することに依拠しており、本論文にヒト心理物理学はない。
独立の機能カルシウムイメージング研究の抄録が背景として「caffeine, which activates five human bitter taste receptors」と明記（Meyerhof 系知見の再言明）。同研究自身のアッセイでも TAS2R43/46 はカフェインに応答した（モザンビオシドより低感度）。5受容体という数の帰属が2020年時点でも研究コミュニティの前提として維持されていることを示す。
カゼイン（1%）のトリプシン12時間消化物をゲル濾過した苦味画分M（2.5 mg/mL、"tastes moderately bitter (equivalent to the bitterness of 0.125 mM of quinine)"）に、hTAS2R1・hTAS2R4・hTAS2R14・hTAS2R16発現細胞が応答し、特にhTAS2R1とhTAS2R4が強く応答。
ヒトTAS2R受容体ファミリーはヒト気道上皮細胞の運動性線毛（T2R4, T2R43, T2R38, T2R46 を同定）。苦味化合物が細胞内カルシウムを上昇させ、線毛打頻度を約25%増加させる（N = 4, P < 0.01）に発現する支持あり
範囲: 培養したヒト初代気道上皮。応答は上皮細胞内で細胞自律的であり、味神経や味知覚を介さない
注記: 検出はマイクロアレイと RT-PCR、および抗 T2R 免疫蛍光による。苦味化合物の正確なモル濃度は second pass で逐語確認できなかったためここには記載しない。単一研究室で、本論文にヒト in vivo の粘液線毛クリアランス測定はない。
逐語: 「We identified T2R4, T2R43, T2R38, and T2R46 in human airway epithelia.」「Denatonium application induced transient, dose-dependent elevations of [Ca2+]i」であり、thujone（T2R14を活性化）、salicin（T2R16を活性化）、キニーネ、ニコチンなど他のいくつかの苦味化合物も[Ca2+]i上昇を惹起した。逐語: 「applying denatonium increased cilia beat frequency ~25% (Fig. 4C, S9) (N = 4. Asterisks indicate P<0.01).」逐語: 「In contrast, in airway epithelia, T2Rs enable cell-autonomous detection of a signal followed by a response in the same cell to eliminate harmful substances.」
限定: Verbatim: Owing to the lack of well-documented antibodies for T2Rs (in particular for mouse T2Rs), the expression profiling of T2Rs in the extraoral tissues has been largely generated using in situ hybridization. Verbatim: This shortcoming could result in trace contamination with genome DNA in the samples; additionally, it casts doubts on the T2R expression profile because T2R genes are intronless and the expression level of T2Rs in extraoral tissues is very low.
範囲: ヒト気道平滑筋細胞と ex vivo の無傷気道、およびマウスの in vivo 気道抵抗（エアロゾル化キニーネ吸入で気道抵抗が正常マウスで 53 +/- 2.96%、オボアルブミン感作マウスで 50 +/- 8% 低下）
Verbatim: Multiple TAS2R transcripts were found to be expressed in human ASM, with the TAS2R10, TAS2R14 and TAS2R31 subtypes being the most highly expressed. Verbatim: The maximal relaxation response to the full beta2AR agonist isoproterenol under these same experimental conditions was a 30 +/- 9.2% reduction in active tension, whereas chloroquine, denatonium and quinine caused a dose-dependent relaxation with a maximal response of >90% loss. Verbatim: agents which bind bitter taste receptors cause marked bronchodilation of intact airways which was ~3-fold greater than that promoted by beta-agonist in intact airways. Verbatim: Inhaled aerosolized quinine decreased airway resistance in normal and sensitized mice by 53 +/- 2.96% and 50 +/- 8%, respectively.
限界: ヒトデータは ex vivo 組織。著者らは第4次ヒト気管支の研究を、弛緩 50-80% の限られた数の研究と記述する。本論文にヒト in vivo 投与はない。
限定: 逐語: 「Although bitter tastants are promising candidates... we would caution that chloroquine and denatonium examined in this study may not be ideal candidates because of the high concentration (i.e., on the order of 100 uM) needed to fully relax precontracted ASM.」
反証: 逐語: However, we subsequently demonstrated through patch-clamp recordings that bitter tastants do not activate large-conductance Ca2+-activated K+ channels but rather inhibit them. Moreover, three different large-conductance Ca2+-activated K+ channel blockers did not affect the bronchodilation induced by bitter tastants. 逐語: There were no detectable local Ca2+ events produced in any of the 14 cells. 逐語: The aforementioned two differences and another difference in which we found that bitter tastants do not activate large-conductance Ca2+-activated K+ channels strongly argue that bitter tastant-induced bronchodilation is highly unlikely to result from the generation of local Ca2+ events, which in turn activate large-conductance Ca2+-activated K+ channel. 代わりに提案されているのは、逐語: TAS2R stimulation activates two opposing Ca2+ signaling pathways via Gbetagamma to increase [Ca2+]i at rest while blocking activated L-type VDCCs to induce bronchodilation of contracted ASM.
限界: 種と標本が反論対象の研究と異なる（新鮮単離した天然マウス細胞 対 培養ヒト細胞）ため、この不一致は同条件での再現失敗ではない。同グループは BK チャネルの論点について2012年に Nature Medicine の matters-arising も発表しているが、今回の調査では読んでいない。
逐語: It is also worth noting that chloroquine, denatonium, and all the bitter tastants examined so far are not endogenous ligands for bitter taste receptors. Hence a major question remains as to whether bitter taste receptors in ASM cells have physiological ligands.
逐語: 「it is not clear what would be the primary or physiological ligands for T2Rs in the systems that do not directly interact with the external environment.」逐語: 「One possibility is that certain bitter-tasting endogenous bioactive compounds that circulate in the bloodstream may serve as physiological ligands for T2Rs in the extraoral cells and tissues.」著者らは締めくくりの節を、逐語で「As this is an emerging area and our understanding is still rudimentary, we discuss the obstacles that the field is encountering.」と書き起こしている。
Verbatim: Owing to the lack of well-documented antibodies for T2Rs (in particular for mouse T2Rs), the expression profiling of T2Rs in the extraoral tissues has been largely generated using in situ hybridization. Verbatim: Most studies use DNA digestion or a DNA-binding column, even though the currently used DNases or filters cannot completely remove genome contamination. Verbatim: This shortcoming could result in trace contamination with genome DNA in the samples; additionally, it casts doubts on the T2R expression profile because T2R genes are intronless and the expression level of T2Rs in extraoral tissues is very low. 腸管については verbatim: no immunostaining evidence exists depicting a colocalization between EEC markers and T2Rs, although alpha-gustducin and TRPM5 have both been detected in serotonin and GLP-1-producing ECCs.
限定: 野生型で作動薬投与後の摂食量は水より49%低かったが、同様の低下はガストデューシン欠損・グレリン受容体欠損マウスでも見られ、著者らは後半相の摂食低下をこれらの経路と独立の機序と解釈している。 逐語: 「In WT mice, food intake was 49% lower in mice that were gavaged with T2R-agonists compared with water. A similar decrease in food intake was observed in gust-/- and GHS-R-/- mice, implying that this effect is mediated via mechanisms independent from alpha-gust」
