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342 results on '"Luo, Huai-Rong"'

29. Direct inhibition of P/Q-type voltage-gated [Ca.sup.2+] channels by Gem does not require a direct Gem/[Ca.sub.v][beta] interaction

Author

Fan, Mingming, Buraei, Zafir, Luo, Huai-Rong, Levenson-Palmer, Rose, and Yang, Jian

Subjects
Electrophysiology -- Research, Calcium channels -- Properties, Biological transport, Active -- Research, Science and technology
Abstract

The Rem, Rem2, Rad, and Gem/Kir (RGK) family of small GTP-binding proteins potently inhibits high voltage-activated (HVA) [Ca.sup.2+] channels, providing a powerful means of modulating neural, endocrine, and muscle functions. The molecular mechanisms of this inhibition are controversial and remain largely unclear. RGK proteins associate directly with [Ca.sup.2+] channel [beta] subunits ([Ca.sub.v][beta]), and this interaction is widely thought to be essential for their inhibitory action. In this study, we investigate the molecular underpinnings of Gem inhibition of P/Q-type [Ca.sup.2+] channels. We find that a purified Gem protein markedly and acutely suppresses P/Q channel activity in inside-out membrane patches, that this action requires [Ca.sub.v][beta] but not the Gem/[Ca.sub.v][beta] interaction, and that Gem coimmunoprecipitates with the P/Q channel [[alpha].sub.1] subunit ([Ca.sub.v][[alpha].sub.1]) in a [Ca.sub.v][beta]-independent manner. By constructing chimeras between P/Q channels and Gem-insensitive low voltage-activated T-type channels, we identify a region encompassing transmembrane segments S1, S2, and S3 in the second homologous repeat of [Ca.sub.v][[alpha].sub.1] critical for Gem inhibition. Exchanging this region between P/Q and T channel [Ca.sub.v][[alpha].sub.1] abolishes Gem inhibition of P/Q channels and confers [Ca.sub.v][beta]-dependent Gem inhibition to a chimeric T channel that also carries the P/Q I-II loop (a cytoplasmic region of [Ca.sub.v][[alpha].sub.1] that binds [Ca.sub.v][beta]). Our results challenge the prevailing view regarding the role of [Ca.sub.v][beta] in RGK inhibition of high voltage-activated [Ca.sup.2+] channels and prompt a paradigm in which Gem directly binds and inhibits [Ca.sub.v][beta]-primed [Ca.sub.v][[alpha].sub.1] on the plasma membrane. [beta] subunit | electrophysiology | modulation | Rem, Rem2, Rad, and Gem/Kir proteins | T-type [Ca.sup.2+] channels doi/ 10.1073/pnas.1007543107

Published
2010

45. Pyrazolo[1,5-a]pyrimidine TRPC6 antagonists for the treatment of gastric cancer

Author

Ding, Mingmin, Wang, Hongbo, Qu, Chunrong, Xu, Fuchun, Zhu, Yingmin, Lv, Guangyao, Lu, Yungang, Zhou, Qingjun, Zhou, Hui, Zeng, Xiaodong, Zhang, Jingwen, Yan, Chunhong, Lin, Jiacheng, Luo, Huai-Rong, Deng, Zixing, Xiao, Yuling, Tian, Jinbin, Zhu, Michael X, Hong, Xuechuan, Lin, Jiacheng [0000-0002-1207-9364], and Apollo - University of Cambridge Repository

Subjects
Mice, Inbred BALB C, Drug discovery, Mice, Nude, Antineoplastic Agents, Apoptosis, Ca(2+) signaling, Xenograft Model Antitumor Assays, TRPC channels, Gene Expression Regulation, Neoplastic, Mice, Anticancer, Pyrimidines, Cell Movement, Stomach Neoplasms, TRPC6 Cation Channel, Tumor Cells, Cultured, Animals, Humans, Pyrazoles, Calcium, Nonselective cation channels, Cell Proliferation
Abstract

Transient receptor potential canonical 6 (TRPC6) proteins form receptor-operated Ca2+-permeable channels, which have been thought to bring benefit to the treatment of diseases, including cancer. However, selective antagonists for TRPC channels are rare and none of them has been tested against gastric cancer. Compound 14a and analogs were synthesized by chemical elaboration of previously reported TRPC3/6/7 agonist 4o. 14a had very weak agonist activity at TRPC6 expressed in HEK293 cells but exhibited strong inhibition on both 4o-mediated and receptor-operated activation of TRPC6 with an IC50 of about 1 μM. When applied to the culture media, 14a suppressed proliferation of AGS and MKN45 cells with IC50 values of 17.1 ± 0.3 and 18.5 ± 1.0 μM, respectively, and inhibited tube formation and migration of cultured human endothelial cells. This anti-tumor effect on gastric cancer was further verified in xenograft models using nude mice. This study has found a new tool compound which shows excellent therapeutic potential against human gastric cancer most likely through targeting TRPC6 channels.

Published
2018

50. Pyrazolo[1,5-a]pyrimidine TRPC6 antagonists for the treatment of gastric cancer

Author

Ding, Mingmin, primary, Wang, Hongbo, additional, Qu, Chunrong, additional, Xu, Fuchun, additional, Zhu, Yingmin, additional, Lv, Guangyao, additional, Lu, Yungang, additional, Zhou, Qingjun, additional, Zhou, Hui, additional, Zeng, Xiaodong, additional, Zhang, Jingwen, additional, Yan, Chunhong, additional, Lin, Jiacheng, additional, Luo, Huai-Rong, additional, Deng, Zixing, additional, Xiao, Yuling, additional, Tian, Jinbin, additional, Zhu, Michael X., additional, and Hong, Xuechuan, additional

Published
2018
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