Biology subjects

Sun, J.-P.

Publications and source records attributed to Sun, J.-P..

2 recordsLinked to original sources

bioRxiv2023

Force-sensing LPHN2 is indispensable for normal hearing and mediates MET in cochleae through Gs and CNGA3 coupling

The conversion of force sensation into electrical signals via mechanoelectrical transduction (MET) is considered the key step in auditory perception. Here, we found that G protein-coupled receptor (GPCR) LPHN2/ADGRL2 was expressed at the tips of stereocilia in cochlear hair cells and was associated with MET channel components. Hair cell-specific LPHN2 deficiency caused hearing loss and impaired MET responses. A specific inhibitor of LPHN2, developed by in silico screening and pharmacological characterization, reversibly blocked the MET response. Mechanistically, administration of force to LPHN2 activated TMC1 through direct interaction and caused conformational changes in TMC1 in vitro. Furthermore, the sensing of force by LPHN2 stimulated Ca2+ responses and neurotransmitter release in hair cells. Finally, hearing loss in LPHN2-deficient mice was reversed by the re-expression of LPHN2-GAIN in cochlear hair cells. The important roles of LPHN2 in auditory perception and a TMC-coupled force sensor indicated that GPCRs could be candidate auditory receptors.

physiology↗

bioRxiv2020

Autonomous sensing the insulin peptide by an olfactory G protein coupled receptor modulates glucose metabolism

Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by {beta} cells(1-3). By screening the expression and functional characterization of olfactory receptors in pancreatic islets, we identified Olfr109 as the receptor to detect insulin peptides. Engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signalling and promoted macrophage proliferation. Remarkably, Olfr109 deficiency alleviated intra-islet inflammatory responses and improved glucose homeostasis in Akita- and HFD-fed mice. We further determined the binding mode between the insB:9-23 and Olfr109. A pepducin-based Olfr109 antagonist improved glucose homeostasis in diabetic and obese mouse models. Collectively, we found that pancreatic {beta} cells use Olfr109 to autonomously detect self-secreted insulin peptides and this detection arrests insulin secretion and crosstalk with macrophages to increase intra-islet inflammation.

physiology↗