Browsing by Author "Ji, Yonghua"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    GPR68 Is a Neuroprotective Proton Receptor in Brain Ischemia
    (Lippincott, Williams & Wilkins, 2020-12) Wang, Tao; Zhou, Guokun; He, Mindi; Xu, Yuanyuan; Rusyniak, W.G.; Xu, Yan; Ji, Yonghua; Simon, Roger P.; Xiong, Zhi-Gang; Zha, Xiang-ming; Obstetrics and Gynecology, School of Medicine
    Brain acidosis is prevalent in stroke and other neurological diseases. Acidosis can have paradoxical injurious and protective effects. The purpose of this study is to determine whether a proton receptor exists in neurons to counteract acidosis-induced injury. Methods: We analyzed the expression of proton-sensitive GPCRs (G protein-coupled receptors) in the brain, examined acidosis-induced signaling in vitro, and studied neuronal injury using in vitro and in vivo mouse models. Results: GPR68, a proton-sensitive GPCR, was present in both mouse and human brain, and elicited neuroprotection in acidotic and ischemic conditions. GPR68 exhibited wide expression in brain neurons and mediated acidosis-induced PKC (protein kinase C) activation. PKC inhibition exacerbated pH 6-induced neuronal injury in a GPR68-dependent manner. Consistent with its neuroprotective function, GPR68 overexpression alleviated middle cerebral artery occlusion–induced brain injury. Conclusions: These data expand our knowledge on neuronal acid signaling to include a neuroprotective metabotropic dimension and offer GPR68 as a novel therapeutic target to alleviate neuronal injuries in ischemia and multiple other neurological diseases.
  • Thumbnail Image
    Item
    Permeation Mechanism of Potassium Ions through the Large Conductance Ca2+-Activated Potassium Channel
    (ACS, 2019-08) Guo, Jingkang; Tan, Zhiyong; Ji, Yonghua; Pharmacology and Toxicology, School of Medicine
    The permeation of the potassium ion (K+) through the selectivity filter (SF) of the large conductance Ca2+-activated potassium (Slo1) channel remains an interesting question to study. Although the mode of K+ entering and leaving the SF has been revealed, the mechanism of K+ passing through the SF is still not clear. In the present study, the pattern of K+ permeation through the SF is investigated by chemical computation and data mining based on the molecular structure of Slo1 from Aplysia californica. Both bond configurations and the free energy of K+s inside the SF was studied using Discovery Studio software. The results suggested that, to accommodate increasing energy levels and to tolerate more K+s, 4-fold symmetric subunits of SF can only move at one direction that is perpendicular to the center axis. In addition, two configurations of chemical bonds between K+s and the SF are usually employed including the chelate configuration under low free energy and the complex configuration under high free energy conditions. Moreover, three patterns of bond configurations for multiple K+s within the SF are used to accommodate the energetic changes of the SF, and each pattern is composed of one or two subconformations. These findings likely resulted from the evolutionary optimization of the protein function of Slo1. The specific conductance and the voltage-gating of the Slo1 channel can be reinterpreted with the permeation mechanism of K+s found in the current study. The permeation mechanism of K+s through the SF can be used to understand the interaction between various toxins and the Slo1 channel, and can be employed to develop new drugs targeting relevant ion channels.