Ancient medicinal plant rosemary contains a highly efficacious and isoform-selective KCNQ potassium channel opener

Voltage-gated potassium (Kv) channels in the KCNQ subfamily serve essential roles in the nervous system, heart, muscle and epithelia. Different heteromeric KCNQ complexes likely serve distinct functions in the brain but heteromer subtype-specific small molecules for research or therapy are lacking. Rosemary (Salvia rosmarinus) is an evergreen plant used medicinally for millennia for nervous system and other disorders. Here, we discovered that rosemary extract is a highly efficacious opener of heteromeric KCNQ3/5 channels, with weak effects on KCNQ2/3. Using functional screening we found that carnosic acid, a phenolic diterpene from rosemary, is a potent, highly efficacious, PIP2 depletion-resistant KCNQ3 opener with lesser effects on KCNQ5 and none on KCNQ1 or KCNQ2. Â Carnosic acid is also highly selective for KCNQ3/5 over KCNQ2/3 heteromers. Medicinal chemistry, in silico docking, and mutagenesis revealed that carboxylate-guanidinium ionic bonding with an S4-5 linker arginine underlies..., ,KCNQ家族亚基的电压门控钾离子（Voltage-gated potassium, Kv）通道在神经系统、心脏、肌肉及上皮组织中发挥至关重要的作用。不同的异聚体KCNQ复合物在大脑中可能行使独特的生理功能，但目前仍缺乏用于研究或治疗的亚型特异性异聚体小分子调节剂。迷迭香（Salvia rosmarinus）是一种常绿植物，数千年来被用于治疗神经系统及其他多种疾病。本研究发现，迷迭香提取物是异聚体KCNQ3/5通道的高效激活剂，对KCNQ2/3通道仅具有微弱调控作用。通过功能筛选实验，我们鉴定出鼠尾草酸——一种来源于迷迭香的酚类二萜——是一种强效且高效的抗磷脂酰肌醇4,5-二磷酸（PIP2）耗竭的KCNQ3通道激活剂，其对KCNQ5的调控作用较弱，对KCNQ1或KCNQ2通道无明显活性。此外，相较于KCNQ2/3异聚体，鼠尾草酸对KCNQ3/5通道具有高度选择性。通过药物化学、计算机虚拟对接与诱变实验，研究团队揭示了其作用机制：羧酸根与胍基通过离子键与S4-5连接域的精氨酸残基相互作用，这是其活性的核心基础，