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  • The cytoprotective effects of glyRs have been reported to


    The cytoprotective effects of glyRs have been reported to associate with the MAPK (JNK, ERK1/2 and p38) signaling pathways [47], [48]. The present study reveals that suppressive phosphorylation of cRaf-MEK1/2-ERK1/2 is initiated by glycine – glyR α2 interactions in cardiomyocytes. As a central regulator, the MEK1/2-ERK1/2 signaling promotes cardiac hypertrophy in the body. This is, in part, by enhancing the transcriptional activity of nuclear factor of activated T XL228 (NFAT) [49]. The p38 and JNK signaling is reported to negatively regulate the cardiac growth response by directly phosphorylating NFAT in the heart [50]. The signaling pathways integrate specific stimuli at the cell membrane and transmit it to intracellular target proteins that are involved in transcription, protein synthesis and protein stability in the myocardium. Therefore, inhibition of MEK1/2- ERK1/2 and activation of p38 and/or JNK might be benefit to the prevention and treatment of maladaptive hypertrophy. Fibrosis is fundamental to pathological remodeling of myocardium in the diseased heart. It is intriguing that there is no glyR in fibroblasts but the expression of glyR α2 in the heart is requisite for antagonistic effect of glycine on the cardiac fibrosis. This might be explained by that glycine itself would not directly impact the production of collagens by fibroblasts. Its direct target for anti-fibrosis seems to be the cardiomyocytes. Glycine could block the stress, such as Ang II, stimulated release of TGF-β and ET-1 by cardiomyocytes. Both TGF-β and ET-1 can stimulate the production of collagens by fibroblasts. Furthermore, it has been reported that TGF-β also can promote XL228 cardiomyocyte hypertrophy [51]. Thus, via an indirect suppression on the production of collagens by fibroblasts and direct effect of TGF-β on cardiomyocytes, glycine may prevent the cardiac fibrosis and development of myocardial remodeling process which is critical in the progression of heart failure [52], [53]. Beyond the inhibition of fibrotic responses, glyR mediated cardiac protection of glycine may have other mechanisms. Glycine can inhibit calcium fluxes in lymphocytes, macrophages, and neutrophils, leading to a decreased secretion of cytokines (e.g. TNF-α). These anti-inflammatory effects are also likely mediated by functional glyRs [6], [54]. A modulating effect of glycine on endothelial cells has been reported via glyRs. [55]. We have found that glycine antagonizes cerebral I/R induced injury by inhibiting extrinsic and intrinsic apoptotic pathways, which is associated with the presence of glyRs [48]. However, similar effect of glycine is not found in the present study. Discovery of the new pharmacological roles of glycine may pave a path to generate a novel therapy differing from the angiotensin-converting enzyme inhibitor and angiotensin type 1 receptor antagonist for treatment of heart failure.
    Conflict of interest statement
    Acknowledgements This work was supported by National Natural Science Foundation of China [81230070 and 91339202 to Qi Chen, 81300211 to Xudong Zhu, 81670263 to Xiaoyu Li, 81370005 to Jingjing Ben]; College Natural Science Foundation of Jiangsu [13KJB310005 to Xudong Zhu]; Jiangsu Province Education Office of the major basic research projects [15KJA310001 to Xiaoyu Li] and the Collaborative Innovation Center For Cardiovascular Disease Translational Medicine of Jiangsu Province.
    Introduction The Cys-loop receptor superfamily constitutes a major class of ligand-gated ion channels involved in fast inhibitory and excitatory neurotransmission throughout the central nervous system and periphery. Members include excitatory cation-selective channels such as the nicotinic acetylcholine receptor and the serotonin type 3 receptor, as well as inhibitory anion-selective channels such as the γ-aminobutyric acid type A and glycine receptors (Thompson et al., 2010). Due to their involvement in a variety of central nervous system disorders, several members of this receptor superfamily serve as targets for compounds in clinical use, as well as investigational agents (Dineley et al., 2015, Nys et al., 2013). In particular, the glycine receptor has been identified as a potential target for a variety of therapeutic applications, including the treatment of inflammatory pain and alcoholism (Foster et al., 2015, Lynch and Callister, 2006, Molander et al., 2005, Molander and Söderpalm, 2005a).