A natural point mutation in the bitter taste receptor TAS2R16 causes inverse agonism of arbutin in lemur gustation

Bitter taste enables the detection of potentially harmful substances and is mediated by bitter taste receptors, TAS2Rs, in vertebrates. Few antagonists and inverse agonists of TAS2Rs have been identified, especially natural compounds. TAS2R16s in humans, apes and Old World monkeys (Catarrhini, Anthropoidea) recognise β-glucoside analogues as specific agonists. Here, we investigated responses of TAS2R16 to β-glucosides in non-anthropoid primates, namely, lemurs (Lemuriformes, Strepsirrhini). Salicin acted as an agonist on lemur TAS2R16. Arbutin acted as an agonist in the ring-tailed lemur (Lemur catta) but as an inverse agonist in black lemur (Eulemur macaco) and black-and-white ruffed lemur (Varecia variegata). We identified a strepsirrhine-specific amino acid substitution responsible for the inverse agonism of arbutin. In a food preference test, salicin bitterness was inhibited by arbutin in the black lemur. Structural modelling revealed this locus was important for a rearrangement of ...苦味感知可用于侦测潜在有害物质，该生理过程由脊椎动物体内的苦味受体TAS2Rs（Taste 2 Receptors）介导。目前已报道的TAS2Rs拮抗剂与反向激动剂数量极少，其中天然来源的化合物更是寥寥。人类、猿类及旧世界猴（狭鼻小目Catarrhini、类人猿亚目Anthropoidea）体内的TAS2R16受体，可将β-葡萄糖苷类似物识别为特异性激动剂。本研究针对非类人猿灵长类——即狐猴类（狐猴下目Lemuriformes、原猴亚目Strepsirrhini）——体内TAS2R16受体对β-葡萄糖苷的应答特征展开了探究。水杨苷可作为狐猴TAS2R16受体的激动剂。熊果苷在环尾狐猴（Lemur catta）体内表现为激动剂，但在黑狐猴（Eulemur macaco）与黑白领狐猴（Varecia variegata）体内则呈现反向激动活性。本研究鉴定出一处原猴亚目特异性的氨基酸替换，该变异是熊果苷产生反向激动作用的分子基础。在食物偏好实验中，黑狐猴体内的水杨苷苦味感知可被熊果苷抑制。结构建模结果表明，该位点对于重排过程具有关键作用（原文后半段未完整给出）。