Institut de Biologia Evolutiva (UPF-CSIC), Universitat Pompeu Fabra, Dr. Aiguader, 88, 08003, Barcelona, Catalonia, Spain.
Laboratory of Molecular Physiology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003, Barcelona, Spain.
Sci Rep. 2020 Dec 2;10(1):20999. doi: 10.1038/s41598-020-78081-z.
TRPP3 (also called PKD2L1) is a nonselective, cation-permeable channel activated by multiple stimuli, including extracellular pH changes. TRPP3 had been considered a candidate for sour sensor in humans, due to its high expression in a subset of tongue receptor cells detecting sour, along with its membership to the TRP channel family known to function as sensory receptors. Here, we describe the functional consequences of two non-synonymous genetic variants (R278Q and R378W) found to be under strong positive selection in an Ethiopian population, the Gumuz. Electrophysiological studies and 3D modelling reveal TRPP3 loss-of-functions produced by both substitutions. R278Q impairs TRPP3 activation after alkalinisation by mislocation of H binding residues at the extracellular polycystin mucolipin domain. R378W dramatically reduces channel activity by altering conformation of the voltage sensor domain and hampering channel transition from closed to open state. Sour sensitivity tests in R278Q/R378W carriers argue against both any involvement of TRPP3 in sour detection and the role of such physiological process in the reported evolutionary positive selection past event.
TRPP3（也称为 PKD2L1）是一种非选择性、阳离子渗透性通道，可被多种刺激激活，包括细胞外 pH 值变化。由于其在一组检测酸味的舌受体细胞中高表达，并且属于已知作为感觉受体的 TRP 通道家族，因此 TRPP3 被认为是人类酸味传感器的候选物。在这里，我们描述了在埃塞俄比亚 Gumuz 人群中发现的两种非同义遗传变异（R278Q 和 R378W）受到强烈正选择的功能后果。电生理研究和 3D 建模揭示了这两种取代产生的 TRPP3 功能丧失。R278Q 通过错误定位细胞外多囊蛋白 mucolipin 结构域中的 H 结合残基，损害 TRPP3 在碱化后的激活。R378W 通过改变电压传感器结构域的构象并阻碍通道从关闭状态向开放状态的转变，极大地降低了通道活性。在 R278Q/R378W 携带者中的酸味敏感性测试表明，TRPP3 既不参与酸味检测，也不参与所报道的过去进化正选择事件中的这种生理过程。
