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Eukaryotic Mechanosensitive Ion Channels
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Over the past ten years, our understanding of mechanotransduction has been greatly expanded due to the groundbreaking discoveries of several bona fide mechanically activated ion channels. Moreover, the physiological and structural/functional studies of these channels are growing rapidly. Yet, there remain some outstanding questions in the field, including a few “holy grails.” First, the molecular identity of the hair cell mechanotransduction channel in the tip link that initiates our sense of hearing is still elusive. Although Piezo2 is found in the hair cells, it is at the base of the stereocilia and its opening is caused by negative pressure near the apical surface and reverse polarity, independently of the tip link [60]. Accumulating evidence indicates the tip link channel as multiple transmembrane protein complexes other than a single MA channel, given that several deafness-related candidates such as TMC1/2, TMIE, and TMHS alone failed to reproduce MA currents in the heterologous system [61,62]. Another long-standing mystery is the molecular identity of the noxious mechanoreceptor detecting the high-threshold forces in sensory neurons, where Piezo2’s role is limited [63]. Much effort has been focused on screening novel MA channels. As a promising future direction, the high-throughput approach offers many advantages relative to conventional hypothesis-driven screening. First, high-throughput approaches enable a full spectrum genomic, non-biased screen for the candidates that are not limited to ion channels. In contrast, conventional screening generates a candidate list based on preferred expression profile analysis or bioinformatics prediction [22], which may miss potential hits. Second, a high-throughput assay such as calcium imaging is time effective, while the conventional electrophysiology recordings require the overexpression or knock-down of candidate genes one by one [22]. As a proof-of-concept, Xu et al. creatively designed a 384-well screening system that applies physiological shear stress on cultured cells, and identified a mechanosensitive GPCR, GPR68, by a focused RNAi library [64]. Future efforts on high-throughput approaches will pave the way to the next breakthrough discoveries. Last but not least, in light of the observation that different classes of MA channels appear to have distinct structural organizations, how diverse groups of MA channels utilize their distinct structural bases to fulfill their designated cellular mechanotransduction function represents a fascinating question to be addressed.
Lactic acid in macrophage polarization: The significant role in inflammation and cancer
Published in International Reviews of Immunology, 2022
Hai-cun Zhou, Wen-wen Yu, Xiao-qin Liang, Xiao-yan Du, Zhi-chang Liu, Jian-ping Long, Guang-hui Zhao, Hong-bin Liu
The signaling transduction function of lactic acid in extracellular space is mediated by the activation of G-protein-coupled receptor GPR [5,23–26]. In physiological environment, lactic acid binds to GPR81, thus inhibiting lipolysis in adipocytes [27]. In cancers, GPR81 is highly expressed in different cancer cell lines, including colon cancer, breast cancer, lung cancer, liver cancer, cervical cancer, and pancreatic cancer [28,29]. In vitro, the expression of GPR81 is associated with the survival, proliferation, migration, invasion and chemotherapy resistance of cancer cells, and participates in the inhibition of anti-tumor immunity by promoting the overexpression of PD-L1 in lung cancer cell lines [28]. During inflammation, lactic acid activated the GPR81-mediated pathway, inhibitted inflammation and reduced organ damage [30]. Another study revealed that high levels of lactic acid produced during childbirth acted on uterine GPR81, and down-regulated the key pro-inflammatory genes [31]. In addition, GPR4, GPR65, GPR68 and GPR132, acted as lactic acid sensors, are activated in acidic tumor microenvironment (TME) due to the low pH value of lactic acid [32]. It remains to be clarified whether the regulation of the lactic acid signaling pathway occurs directly through GPR-lactic acid interaction or through conformational modification of the receptor induced by lactic acidosis.
A review of antibody-based therapeutics targeting G protein-coupled receptors: an update
Published in Expert Opinion on Biological Therapy, 2020
Research activity in the oncology therapeutic area has increased dramatically, virtually doubling since 2017 [11], which is perhaps not surprising given the current focus on immuno-oncology therapeutic strategies and the potential for combination therapy with checkpoint inhibitors, small molecules, etc. A recent transcriptomics analysis demonstrated that most tumor types differentially express greater than 50 GPCRs, including many targets for approved drugs, but also a number of GPCRs largely unrecognized as targets of interest in cancer [47] and thereby adding to the growing list of these targeting opportunities. Such GPCRomics approaches [48] have highlighted potential therapeutic targets, such as GPR68 [47,49]. Research tools will be invaluable to further validate these potential targets for therapeutic relevance [50].