2. Academic Validation
  3. CCT128930 is a novel and potent antagonist of TRPM7 channel

CCT128930 is a novel and potent antagonist of TRPM7 channel

  • Biochem Biophys Res Commun. 2021 Jun 30;560:132-138. doi: 10.1016/j.bbrc.2021.04.119.
Ziyue Guan 1,  Xueqin Chen 2,  Sui Fang 2,  Yonghua Ji 3,  Zhaobing Gao 4,  Yueming Zheng 5
Affiliations

Affiliations

  • 1 Shanghai University, Shanghai, 200444, China; Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 2 Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 3 Shanghai University, Shanghai, 200444, China.
  • 4 Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: zbgao@simm.ac.cn.
  • 5 Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: zhengyueming@simm.ac.cn.
PMID: 33989904 DOI: 10.1016/j.bbrc.2021.04.119
Abstract

Transient receptor potential melastatin 7 (TRPM7) channels represent a major magnesium (Mg2+)-uptake component in mammalian cells and are negatively modulated by internal Mg2+. However, few TRPM7 modulators were identified so far, which hindered the understanding of the TRPM7 channel functions. In this study, we identified that CCT128930, an ATP-competitive protein kinase B inhibitor reported previously, was a potent TRPM7 channel antagonist. The inhibition of CCT128930 on TRPM7 was independent of intracellular Mg2+. In the absence and presence of 300 μM Mg2+ in pipette solution, the IC50 values were 0.86 ± 0.11 μM and 0.63 ± 0.09 μM, respectively. Subtype selectivity data showed that CCT128930 preferentially inhibited TRPM7 channels compared to TRPM6 and TRPM8 isoforms. In addition, CCT128930 was found to be able to reduce the endogenous TRPM7-like currents in SH-SY5Y neuroblastoma cells. At last, multiple residues in the superficial part of the TRPM7 selectivity filter were identified to be critical for the inhibitory activity of CCT128930 which are different from the determinants of Mg2+ and reported TRPM7 antagonists. Our results indicated that CCT128930 is a novel and potent TRPM7 channel antagonist.

Keywords

Antagonist; CCT128930; Molecular determinants; TRPM7.

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