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Current Vascular Pharmacology

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ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

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Role of Glycine and Glycine Receptors in Vascular Endothelium: A New Perspective for the Management of the Post-Ischemic Injury

Author(s): Ricardo Valdés-Jorquera, Leticia Oviedo-Castro, Carolina A. Oliva* and Trinidad A. Mariqueo*

Volume 20, Issue 3, 2022

Published on: 27 July, 2022

Page: [221 - 229] Pages: 9

DOI: 10.2174/1570161120666220720101352

Price: $65

Abstract

Glycine Receptors (GlyRs) are cell-surface transmembrane proteins that belong to the Cysloop ligand-gated ion channels superfamily (Cys-loop LGICs). Functional glycine receptors are conformed only by α-subunits (homomeric channels) or by α- and β-subunits (heteromeric channels). The role of glycine as a cytoprotective is widely studied. New information about glycine modulation of vascular endothelial cells (ECs) function emerged last year. Glycine and its receptors are recognized to play a role as neurovascular protectors by a mechanism that involves α2GlyRs. Interestingly, the expression of α2GlyRs reduces after stroke injury. However, glycine reverses the inhibition of α2GlyRs by a mechanism involving the VEGF/pSTAT3 signaling. On the other hand, consistent evidence has demonstrated that ECs participate actively in the innate and adaptive immunological response. We recently reported that GlyRs are modulated by interleukin-1β, suggesting new perspectives to explain the immune modulation of vascular function in pathological conditions such as cerebrovascular stroke. In this work, we distinguish the role of glycine and the allosteric modulation of glycine receptors as a new therapeutic target to confront post-ischemic injury.

Keywords: Glycine, GlyRα2, GlyT1, ischemic injury, angiogenesis, PI3K/AKT/mTOR, allosteric modulation, VEGF/ pSTAT3.

« Previous Next »
[1]
Guo D, Murdoch CE, Xu H, et al. Vascular endothelial growth factor signaling requires glycine to promote angiogenesis. Sci Rep 2017; 7(1): 14749.
[http://dx.doi.org/10.1038/s41598-017-15246-3] [PMID: 29116138]
[2]
Weinberg JM, Bienholz A, Venkatachalam MA. The role of glycine in regulated cell death. Cell Mol Life Sci 2016; 73(11-12): 2285-308.
[http://dx.doi.org/10.1007/s00018-016-2201-6] [PMID: 27066896]
[3]
Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005; 438(7070): 967-74.
[http://dx.doi.org/10.1038/nature04483] [PMID: 16355214]
[4]
Risau W. Mechanisms of angiogenesis. Nature 1997; 386(6626): 671-4.
[http://dx.doi.org/10.1038/386671a0] [PMID: 9109485]
[5]
Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 2007; 8(6): 464-78.
[http://dx.doi.org/10.1038/nrm2183] [PMID: 17522591]
[6]
Chen Z, Wang X, Liao H, et al. Glycine attenuates cerebrovascular remodeling via glycine receptor alpha 2 and vascular endothelial growth factor receptor 2 after stroke. Am J Transl Res 2020; 12(10): 6895-907.
[PMID: 33194080]
[7]
Tsuji-Tamura K, Sato M, Fujita M, Tamura M. Glycine exerts dose-dependent biphasic effects on vascular development of zebrafish embry-os. Biochem Biophys Res Commun 2020; 527(2): 539-44.
[http://dx.doi.org/10.1016/j.bbrc.2020.04.098] [PMID: 32423801]
[8]
Yao W, Ji F, Chen Z, et al. Glycine exerts dual roles in ischemic injury through distinct mechanisms. Stroke 2012; 43(8): 2212-20.
[http://dx.doi.org/10.1161/STROKEAHA.111.645994] [PMID: 22693133]
[9]
Rajendra S, Lynch JW, Schofield PR. The glycine receptor. Pharmacol Ther 1997; 73(2): 121-46.
[http://dx.doi.org/10.1016/S0163-7258(96)00163-5] [PMID: 9131721]
[10]
Hall JC. Review: Glycine. JPEN J Parenter Enteral Nutr 1998; 22(6): 393-8.
[http://dx.doi.org/10.1177/0148607198022006393]
[11]
Cai CC, Zhu JH, Ye LX, et al. Glycine protects against hypoxic-ischemic brain injury by regulating mitochondria-mediated autophagy via the AMPK Pathway. Oxid Med Cell Longev 2019; 2019: 4248529.
[http://dx.doi.org/10.1155/2019/4248529] [PMID: 30881590]
[12]
Betz H, Laube B. Glycine receptors: Recent insights into their structural organization and functional diversity. J Neurochem 2006; 97(6): 1600-10.
[http://dx.doi.org/10.1111/j.1471-4159.2006.03908.x] [PMID: 16805771]
[13]
Galaz P, Barra R, Figueroa H, Mariqueo T. Advances in the pharmacology of lGICs auxiliary subunits. Pharmacol Res 2015; 101: 65-73.
[http://dx.doi.org/10.1016/j.phrs.2015.07.026] [PMID: 26255765]
[14]
Yevenes GE, Zeilhofer HU. Allosteric modulation of glycine receptors. Br J Pharmacol 2011; 164(2): 224-36.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01471.x] [PMID: 21557733]
[15]
Dutertre S, Becker C-M, Betz H. Inhibitory glycine receptors: An update. J Biol Chem 2012; 287(48): 40216-23.
[http://dx.doi.org/10.1074/jbc.R112.408229] [PMID: 23038260]
[16]
Aguayo LG, van Zundert B, Tapia JC, Carrasco MA, Alvarez FJ. Changes on the properties of glycine receptors during neuronal develop-ment. Brain Res Brain Res Rev 2004; 47(1-3): 33-45.
[http://dx.doi.org/10.1016/j.brainresrev.2004.06.007] [PMID: 15572161]
[17]
Farley N-MM, Mihic SJ. Allosteric modulation of the glycine receptor activated by agonists differing in efficacy. Brain Res 2015; 1606: 95-101.
[http://dx.doi.org/10.1016/j.brainres.2015.02.024] [PMID: 25721789]
[18]
Laube B, Maksay G, Schemm R, Betz H. Modulation of glycine receptor function: A novel approach for therapeutic intervention at inhibitory synapses? Trends Pharmacol Sci 2002; 23(11): 519-27.
[http://dx.doi.org/10.1016/S0165-6147(02)02138-7] [PMID: 12413807]
[19]
Kumar A, Basak S, Rao S, et al. Mechanisms of activation and desensitization of full-length glycine receptor in lipid nanodiscs. Nat Commun 2020; 11(1): 3752.
[http://dx.doi.org/10.1038/s41467-020-17364-5] [PMID: 32719334]
[20]
Wang D-S, Mangin J-M, Moonen G, Rigo J-M, Legendre P. Mechanisms for picrotoxin block of α2 homomeric glycine receptors. J Biol Chem 2006; 281(7): 3841-55.
[http://dx.doi.org/10.1074/jbc.M511022200] [PMID: 16344549]
[21]
Burgos CF, Yévenes GE, Aguayo LG. Structure and pharmacologic modulation of inhibitory glycine receptors. Mol Pharmacol 2016; 90(3): 318-25.
[http://dx.doi.org/10.1124/mol.116.105726] [PMID: 27401877]
[22]
Solorza J, Oliva CA, Castillo K, et al. Effects of interleukin-1β in glycinergic transmission at the central amygdala. Front Pharmacol 2021; 12(March): 613105.
[http://dx.doi.org/10.3389/fphar.2021.613105] [PMID: 33746753]
[23]
Tang B, Lummis SCR. Multiple regions in the extracellular domain of the glycine receptor determine receptor activity. J Biol Chem 2018; 293(36): 13889-96.
[http://dx.doi.org/10.1074/jbc.RA118.003088] [PMID: 29941455]
[24]
Grudzinska J, Schemm R, Haeger S, et al. The β subunit determines the ligand binding properties of synaptic glycine receptors. Neuron 2005; 45(5): 727-39.
[http://dx.doi.org/10.1016/j.neuron.2005.01.028] [PMID: 15748848]
[25]
Lobo IA, Harris RA, Trudell JR. Cross-linking of sites involved with alcohol action between transmembrane segments 1 and 3 of the glycine receptor following activation. J Neurochem 2008; 104(6): 1649-62.
[http://dx.doi.org/10.1111/j.1471-4159.2007.05090.x] [PMID: 18036150]
[26]
Perkins DI, Trudell JR, Asatryan L, Davies DL, Alkana RL. Charge and geometry of residues in the loop 2 β hairpin differentially affect ago-nist and ethanol sensitivity in glycine receptors. J Pharmacol Exp Ther 2012; 341(2): 543-51.
[http://dx.doi.org/10.1124/jpet.111.190942] [PMID: 22357974]
[27]
Yang Z, Aubrey KR, Alroy I, Harvey RJ, Vandenberg RJ, Lynch JW. Subunit-specific modulation of glycine receptors by cannabinoids and N-arachidonyl-glycine. Biochem Pharmacol 2008; 76(8): 1014-23.
[http://dx.doi.org/10.1016/j.bcp.2008.07.037] [PMID: 18755158]
[28]
Xiong W, Cheng K, Cui T, et al. Cannabinoid potentiation of glycine receptors contributes to cannabis-induced analgesia. Nat Chem Biol 2011; 7(5): 296-303.
[http://dx.doi.org/10.1038/nchembio.552] [PMID: 21460829]
[29]
Xiong W, Cui T, Cheng K, et al. Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors. J Exp Med 2012; 209(6): 1121-34.
[http://dx.doi.org/10.1084/jem.20120242] [PMID: 22585736]
[30]
Xiong W, Wu X, Li F, et al. A common molecular basis for exogenous and endogenous cannabinoid potentiation of glycine receptors. J Neurosci 2012; 32(15): 5200-8.
[http://dx.doi.org/10.1523/JNEUROSCI.6347-11.2012] [PMID: 22496565]
[31]
Miller PS, Harvey RJ, Smart TG. Differential agonist sensitivity of glycine receptor α2 subunit splice variants. Br J Pharmacol 2004; 143(1): 19-26.
[http://dx.doi.org/10.1038/sj.bjp.0705875] [PMID: 15302677]
[32]
Chirila AM, Brown TE, Bishop RA, Bellono NW, Pucci FG, Kauer JA. Long-term potentiation of glycinergic synapses triggered by interleukin 1β. Proc Natl Acad Sci USA 2014; 111(22): 8263-8.
[http://dx.doi.org/10.1073/pnas.1401013111] [PMID: 24830427]
[33]
Kawasaki Y, Zhang L, Cheng J-K, Ji R-R. Cytokine mechanisms of central sensitization: Distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 2008; 28(20): 5189-94.
[http://dx.doi.org/10.1523/JNEUROSCI.3338-07.2008] [PMID: 18480275]
[34]
Patrizio A, Renner M, Pizzarelli R, Triller A, Specht CG. Alpha subunit-dependent glycine receptor clustering and regulation of synaptic re-ceptor numbers. Sci Rep 2017; 7(1): 10899.
[http://dx.doi.org/10.1038/s41598-017-11264-3] [PMID: 28883437]
[35]
Allan SM, Parker LC, Collins B, Davies R, Luheshi GN, Rothwell NJ. Cortical cell death induced by IL-1 is mediated via actions in the hypo-thalamus of the rat. Proc Natl Acad Sci USA 2000; 97(10): 5580-5.
[http://dx.doi.org/10.1073/pnas.090464197] [PMID: 10779559]
[36]
Stroemer RP, Rothwell NJ. Exacerbation of ischemic brain damage by localized striatal injection of interleukin-1β in the rat. J Cereb Blood Flow Metab 1998; 18(8): 833-9.
[http://dx.doi.org/10.1097/00004647-199808000-00003] [PMID: 9701344]
[37]
Yamasaki Y, Matsuura N, Shozuhara H, Onodera H, Itoyama Y, Kogure K. Interleukin-1 as a pathogenetic mediator of ischemic brain dam-age in rats. Stroke 1995; 26(4): 676-80.
[http://dx.doi.org/10.1161/01.STR.26.4.676] [PMID: 7709417]
[38]
Eulenburg V, Armsen W, Betz H, Gomeza J. Glycine transporters: Essential regulators of neurotransmission. Trends Biochem Sci 2005; 30(6): 325-33.
[http://dx.doi.org/10.1016/j.tibs.2005.04.004] [PMID: 15950877]
[39]
Huang B, Xie Q, Lu X, et al. GlyT1 inhibitor NFPS exerts neuroprotection via GlyR alpha1 subunit in the rat model of transient focal cerebral ischaemia and reperfusion. Cell Physiol Biochem 2016; 38(5): 1952-62.
[http://dx.doi.org/10.1159/000445556] [PMID: 27161043]
[40]
Abela CB, Homer-Vanniasinkham S. Clinical implications of ischaemia-reperfusion injury. Pathophysiology 2003; 9(4): 229-40.
[http://dx.doi.org/10.1016/S0928-4680(03)00025-7] [PMID: 14567926]
[41]
Wu M-Y, Yiang G-T, Liao W-T, et al. Current mechanistic concepts in ischemia and reperfusion injury. Cell Physiol Biochem 2018; 46(4): 1650-67.
[http://dx.doi.org/10.1159/000489241] [PMID: 29694958]
[42]
Nishimura Y, Lemasters JJ. Glycine blocks opening of a death channel in cultured hepatic sinusoidal endothelial cells during chemical hy-poxia. Cell Death Differ 2001; 8(8): 850-8.
[http://dx.doi.org/10.1038/sj.cdd.4400877] [PMID: 11526438]
[43]
Van den Eynden J, Ali SS, Horwood N, et al. Glycine and glycine receptor signalling in non-neuronal cells. Front Mol Neurosci 2009; 2: 9.
[http://dx.doi.org/10.3389/neuro.02.009.2009] [PMID: 19738917]
[44]
Eltzschig HK, Eckle T. Ischemia and reperfusion-from mechanism to translation. Nat Med 2011; 17(11): 1391-401.
[http://dx.doi.org/10.1038/nm.2507] [PMID: 22064429]
[45]
Szabó C, Zingarelli B, Salzman AL. Role of poly-ADP ribosyltransferase activation in the vascular contractile and energetic failure elicited by exogenous and endogenous nitric oxide and peroxynitrite. Circ Res 1996; 78(6): 1051-63.
[http://dx.doi.org/10.1161/01.RES.78.6.1051] [PMID: 8635236]
[46]
Ogawa S, Gerlach H, Esposito C, Pasagian-Macaulay A, Brett J, Stern D. Hypoxia modulates the barrier and coagulant function of cultured bovine endothelium. Increased monolayer permeability and induction of procoagulant properties. J Clin Invest 1990; 85(4): 1090-8.
[http://dx.doi.org/10.1172/JCI114540] [PMID: 2156893]
[47]
Zhang Y, Ikejima K, Honda H, Kitamura T, Takei Y, Sato N. Glycine prevents apoptosis of rat sinusoidal endothelial cells caused by depri-vation of vascular endothelial growth factor. Hepatology 2000; 32(3): 542-6.
[http://dx.doi.org/10.1053/jhep.2000.16605] [PMID: 10960447]
[48]
Shibuya M. Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: A crucial target for anti- and pro-angiogenic therapies. Genes Cancer 2011; 2(12): 1097-105.
[http://dx.doi.org/10.1177/1947601911423031] [PMID: 22866201]
[49]
Shima DT, Adamis AP, Ferrara N, et al. Hypoxic induction of endothelial cell growth factors in retinal cells: Identification and characteriza-tion of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med 1995; 1(2): 182-93.
[http://dx.doi.org/10.1007/BF03401566] [PMID: 8529097]
[50]
Ziello JE, Jovin IS, Huang Y. Hypoxia-Inducible Factor (HIF)-1 regulatory pathway and its potential for therapeutic intervention in malignan-cy and ischemia. Yale J Biol Med 2007; 80(2): 51-60.
[PMID: 18160990]
[51]
Shi Y-H, Fang W-G. Hypoxia-inducible factor-1 in tumour angiogenesis. World J Gastroenterol 2004; 10(8): 1082-7.
[http://dx.doi.org/10.3748/wjg.v10.i8.1082] [PMID: 15069703]
[52]
Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003; 3(10): 721-32.
[http://dx.doi.org/10.1038/nrc1187] [PMID: 13130303]
[53]
Palazon A, Goldrath AW, Nizet V, Johnson RS. HIF transcription factors, inflammation, and immunity. Immunity 2014; 41(4): 518-28.
[http://dx.doi.org/10.1016/j.immuni.2014.09.008] [PMID: 25367569]
[54]
Liu R, Liao X-Y, Pan M-X, et al. Glycine exhibits neuroprotective effects in ischemic stroke in rats through the inhibition of M1 microglial polarization via the NF-κB p65/Hif-1α signaling pathway. J Immunol 2019; 202(6): 1704-14.
[http://dx.doi.org/10.4049/jimmunol.1801166] [PMID: 30710045]
[55]
Morello F, Perino A, Hirsch E. Phosphoinositide 3-kinase signalling in the vascular system. Cardiovasc Res 2009; 82(2): 261-71.
[http://dx.doi.org/10.1093/cvr/cvn325] [PMID: 19038971]
[56]
Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci 2011; 4: 51.
[http://dx.doi.org/10.3389/fnmol.2011.00051] [PMID: 22144946]
[57]
Zhou H, Huang S. The complexes of mammalian target of rapamycin. Curr Protein Pept Sci 2010; 11(6): 409-24.
[http://dx.doi.org/10.2174/138920310791824093] [PMID: 20491627]
[58]
Ziegler ME, Hatch MMS, Wu N, Muawad SA, Hughes CCW. mTORC2 mediates CXCL12-induced angiogenesis. Angiogenesis 2016; 19(3): 359-71.
[http://dx.doi.org/10.1007/s10456-016-9509-6] [PMID: 27106789]
[59]
Bellon A, Luchino J, Haigh K, et al. VEGFR2 (KDR/Flk1) signaling mediates axon growth in response to semaphorin 3E in the developing brain. Neuron 2010; 66(2): 205-19.
[http://dx.doi.org/10.1016/j.neuron.2010.04.006] [PMID: 20434998]
[60]
Salcedo R, Oppenheim JJ. Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation 2003; 10(3-4): 359-70.
[http://dx.doi.org/10.1080/mic.10.3-4.359.370] [PMID: 12851652]
[61]
Niu G, Wright KL, Huang M, et al. Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 2002; 21(13): 2000-8.
[http://dx.doi.org/10.1038/sj.onc.1205260] [PMID: 11960372]
[62]
Bartoli M, Gu X, Tsai NT, et al. Vascular endothelial growth factor activates STAT proteins in aortic endothelial cells. J Biol Chem 2000; 275(43): 33189-92.
[http://dx.doi.org/10.1074/jbc.C000318200] [PMID: 10961983]
[63]
Terman BI, Carrion ME, Kovacs E, Rasmussen BA, Eddy RL, Shows TB. Identification of a new endothelial cell growth factor receptor tyro-sine kinase. Oncogene 1991; 6(9): 1677-83.
[PMID: 1656371]
[64]
Jung JE, Lee HG, Cho IH, et al. STAT3 is a potential modulator of HIF-1-mediated VEGF expression in human renal carcinoma cells. FASEB J 2005; 19(10): 1296-8.
[http://dx.doi.org/10.1096/fj.04-3099fje] [PMID: 15919761]
[65]
Yu JSL, Cui W. Proliferation, survival and metabolism: The role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development 2016; 143(17): 3050-60.
[http://dx.doi.org/10.1242/dev.137075] [PMID: 27578176]
[66]
Heidari R, Ghanbarinejad V, Mohammadi H, et al. Mitochondria protection as a mechanism underlying the hepatoprotective effects of gly-cine in cholestatic mice. Biomed Pharmacother 2018; 97: 1086-95.
[http://dx.doi.org/10.1016/j.biopha.2017.10.166] [PMID: 29136945]
[67]
Ismayilov V, Aksoy DY, Sayinalp N, Haznedaroğlu IC, Aksoy MC. Increased soluble selectins as a reflection of activated platelets and endo-thelium in Legg-Calve-Perthes disease. J Pediatr Hematol Oncol 2014; 36(7): e410-1.
[http://dx.doi.org/10.1097/MPH.0000000000000203] [PMID: 25000467]

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