Kynurenic acid (KynA) is tissue protective in cardiac, cerebral, renal, and retinal ischemia models, but the mechanism is unknown. KynA can bind to multiple receptors, including the aryl hydrocarbon receptor, the a7 nicotinic acetylcholine receptor (a7nAChR), multiple ionotropic glutamate receptors, and the orphan G protein–coupled receptor GPR35. Here, we show that GPR35 activation was necessary and sufficient for ischemic protection by KynA. When bound by KynA, GPR35 activated G i - and G 12/13 -coupled signaling and trafficked to the outer mitochondria membrane, where it bound, apparantly indirectly, to ATP synthase inhibitory factor subunit 1 (ATPIF1). Activated GPR35, in an ATPIF1-dependent and pertussis toxin–sensitive manner, induced ATP synthase dimerization, which prevented ATP loss upon ischemia. These findings provide a rationale for the development of specific GPR35 agonists for the treatment of ischemic diseases.

中文翻译：

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G 蛋白偶联受体 35 激动剂的线粒体重塑和缺血保护


犬尿酸 (KynA) 在心脏、脑、肾和视网膜缺血模型中具有组织保护作用，但其机制尚不清楚。 KynA 可以结合多种受体，包括芳烃受体、a7 烟碱乙酰胆碱受体 (a7nAChR)、多种离子型谷氨酸受体和孤儿 G 蛋白偶联受体 GPR35。在这里，我们证明 GPR35 激活对于 KynA 的缺血保护是必要且充分的。当与 KynA 结合时，GPR35 激活 G我- 和G 12/13 -耦合信号传导并转运至线粒体外膜，显然是间接与 ATP 合酶抑制因子亚基 1 (ATPIF1) 结合。激活的 GPR35 以 ATPIF1 依赖性和百日咳毒素敏感的方式诱导 ATP 合酶二聚化，从而防止缺血时 ATP 损失。这些发现为开发用于治疗缺血性疾病的特异性 GPR35 激动剂提供了理论依据。