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Role of group I metabotropic glutamate receptors, mGluR1/mGluR5, in connexin43 phosphorylation and inhibition of gap junctional intercellular communication in H9c2 cardiomyoblast cells

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Abstract

Group I metabotropic glutamate receptors, mGluR1 and mGluR5, are associated with sympathetic nerve activity. Sympathetic nerve stimulation exerts a crucial effect on modulating phosphorylation status and distribution of connexin43 (Cx43) in rat heart. Hence, mGluR1 and mGluR5 have an indirect effect on regulating the function of gap junction channels, which is affected by the availability of Cx43 protein. Additionally, it has been demonstrated that mGluR1/5 are present in ventricular myocardium in particular intercalated disks where Cx43 is the principal component of ventricular gap junction channels. We, therefore, hypothesized that mGluR1/5 might regulate Cx43 phosphorylation and gap junctional intercellular communication (GJIC) directly, independent of sympathetic nerve stimulation. After documenting the presence of mGluR1 and mGluR5 in H9c2 cardiomyoblast cells, addition of the selective mGluR1/5 agonist (S)-3,5-dihydroxyphenylglycine hydrate (DHPG) induced Cx43 phosphorylation and GJIC inhibition in both concentration- and time-dependent manner. The effects of DHPG were abolished by the mGluR1 antagonist LY367385 and the specific inhibitor of MEK1, PD98059 which also reduced phosphorylation of extracellular-signal-regulated protein kinase 1/2 (ERK1/2); but not by the mGluR5 antagonist 6-methyl-2-(phenylethynyl) pyridine hydrochloride or the selective inhibitor of protein kinase C (PKC). In conclusion, in H9c2 cardiomyoblast cells mGluR1 increases Cx43 phosphorylation level and suppresses GJIC involving ERK1/2 but not PKC.

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Acknowledgments

This study was sponsored by the Natural Science Foundation of China (81270238), the Scientific Research Foundation for the Doctoral Degree, State Education Ministry of China (20100131110059) and supported by the Scientific Development Plan of Shandong Province of China (2012G0021850).

Conflict of interest

We do not have any competing interests in this research.

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Authors and Affiliations

  1. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Qilu Hospital of Shandong University, 107 Wen Hua Xi Lu, Jinan, 250012, China

    Fei Xie, Shao-lei Yi, Li Hao, Yun Zhang & Jing-quan Zhong

  2. School of Medicine, Shandong University, Jinan, China

    Fei Xie, Shao-lei Yi & Li Hao

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  1. Fei Xie
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  2. Shao-lei Yi
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Correspondence to Jing-quan Zhong.

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Xie, F., Yi, Sl., Hao, L. et al. Role of group I metabotropic glutamate receptors, mGluR1/mGluR5, in connexin43 phosphorylation and inhibition of gap junctional intercellular communication in H9c2 cardiomyoblast cells. Mol Cell Biochem 400, 213–222 (2015). https://doi.org/10.1007/s11010-014-2278-x

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