Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, UT, 84132, USA.
Department of Neurobiology, University of Utah, Salt Lake City, UT, 84132, USA.
Sci Rep. 2023 May 1;13(1):7075. doi: 10.1038/s41598-023-34361-y.
Adenylyl cyclase 6 (AC6) synthesizes second messenger cAMP in G protein-coupled receptor (GPCR) signaling. In cochlear hair cells, AC6 distribution relies on an adhesion GPCR, ADGRV1, which is associated with Usher syndrome (USH), a condition of combined hearing and vision loss. ADGRV1 is a component of the USH type 2 (USH2) protein complex in hair cells and photoreceptors. However, the role of AC6 in the inner ear and retina has not been explored. Here, we found that AC6 distribution in hair cells depends on the USH2 protein complex integrity. Several known AC6 regulators and effectors, which were previously reported to participate in ADGRV1 signaling in vitro, are localized to the stereociliary compartments that overlap with AC6 distribution in hair cells. In young AC6 knockout (Adcy6) mice, the activity of cAMP-dependent protein kinase, but not Akt kinase, is altered in cochleas, while both kinases are normal in vestibular organs. Adult Adcy6 mice however exhibit normal hearing function. AC6 is expressed in mouse retinas but rarely in photoreceptors. Adcy6 mice have slightly enhanced photopic but normal scotopic vision. Therefore, AC6 may participate in the ADGRV1 signaling in hair cells but AC6 is not essential for cochlear and retinal development and maintenance.
腺苷酸环化酶 6（AC6）在 G 蛋白偶联受体（GPCR）信号中合成第二信使 cAMP。在内耳毛细胞中，AC6 的分布依赖于粘附 GPCR ADGRV1，ADGRV1 与聋病（USH）有关，这是一种听力和视力丧失的综合征。ADGRV1 是毛细胞和光感受器中 USH2 蛋白复合物的组成部分。然而，AC6 在内耳和视网膜中的作用尚未得到探索。在这里，我们发现毛细胞中 AC6 的分布依赖于 USH2 蛋白复合物的完整性。以前在体外报道参与 ADGRV1 信号的几种已知的 AC6 调节剂和效应物，定位于与毛细胞中 AC6 分布重叠的静纤毛隔室中。在年轻的 AC6 敲除（Adcy6）小鼠中，cAMP 依赖性蛋白激酶的活性，但不是 Akt 激酶，在耳蜗中发生改变，而这两种激酶在前庭器官中均正常。然而，成年 Adcy6 小鼠具有正常的听力功能。AC6 在小鼠视网膜中表达，但在光感受器中很少表达。Adcy6 小鼠的明视觉略有增强，但暗视觉正常。因此，AC6 可能参与毛细胞中的 ADGRV1 信号，但 AC6 对于耳蜗和视网膜的发育和维持不是必需的。
