Calcium channels are involved in EphB/ephrinB reverse signaling‑induced apoptosis in a rat chronic ocular hypertension model

Dong,Lingdan; Cheng,Xianglin; Zhou,Long; Hu,Yanhong

doi:10.3892/mmr.2017.8162

Calcium channels are involved in EphB/ephrinB reverse signaling‑induced apoptosis in a rat chronic ocular hypertension model

Authors:
- Lingdan Dong
- Xianglin Cheng
- Long Zhou
- Yanhong Hu
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Affiliations: Central Laboratory, First People's Hospital of Jingzhou, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China , Department of Neurology, First People's Hospital of Jingzhou, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China, Department of Pathology, First People's Hospital of Jingzhou, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434000, P.R. China, Nursing Department of Medical School of Yangtze University, Jingzhou, Hubei 434000, P.R. China
Published online on: November 27, 2017 https://doi.org/10.3892/mmr.2017.8162
Pages: 2465-2471
Copyright: © Dong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Erythropoietin-producing hepatocyte receptor B (EphB)/ephrinB reverse signaling has been revealed to be activated in chronic ocular hypertension (COH) by increasing the apoptosis of retinal ganglion cells (RGCs). However, the exact mechanism is not well understood. The present study investigated the involvement of Ca2+ channels in the apoptosis of RGCs induced by EphB/ephrinB reverse signaling in a rat CHO model, which was established by cauterizing 3 out of the 4 episcleral veins. The expression levels of four voltage‑gated Ca2+ channel subunits (Cav3.1‑3.3 and Cav1.2) were detected using immunofluorescence and western blot analysis. TUNEL staining was performed to assess RGC apoptosis following an injection with the T type Ca2+ channel blocker. Ca2+ channels, mainly the T type, were upregulated in COH rat retinas when compared with the sham group (P<0.01). Additionally, the Cav3.2 subunit of T type calcium channels was predominantly expressed in Müller cells and RGCs, such as ephrinB2. Furthermore, an intravitreal injection of the Ca2+ channel blocker Mibefradil (3 µM) reduced EphB2‑fragment crystallizable region‑induced RGC apoptosis in normal rats. Thus, the results suggest that Ca2+ channels in a COH model may be a pathway involved in ephrinB/EphB signaling‑induced RGC apoptosis.

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1	Pasquale EB: Eph receptor signaling casts a wide net on cell behavior. Nat Rev Mol Cell Biol. 6:462–475. 2005. View Article : Google Scholar : PubMed/NCBI
2	Yamaguchi Y and Pasquale EB: Eph receptors in the adult brain. Curr Opin Neurobiol. 14:288–296. 2004. View Article : Google Scholar : PubMed/NCBI
3	Pasquale EB: Eph-ephrin bidirectional signaling in physiology and disease. Cell. 133:38–52. 2008. View Article : Google Scholar : PubMed/NCBI
4	Egea J and Klein R: Bidirectional Eph-ephrin signaling during axon guidance. Trends Cell Biol. 17:230–238. 2007. View Article : Google Scholar : PubMed/NCBI
5	Himanen JP, Saha N and Nikolov DB: Cell-cell signaling via Eph receptors and ephrins. Curr Opin Cell Biol. 19:534–542. 2007. View Article : Google Scholar : PubMed/NCBI
6	Klein R: Bidirectional modulation of synaptic functions by Eph/ephrin signaling. Nat Neurosci. 12:15–20. 2009. View Article : Google Scholar : PubMed/NCBI
7	Chen Y, Fu AK and Ip NY: Eph receptors at synapses: Implications in neurodegenerative diseases. Cell Signal. 24:606–611. 2012. View Article : Google Scholar : PubMed/NCBI
8	Lai KO and Ip NY: Synapse development and plasticity: Roles of ephrin/Eph receptor signaling. Curr Opin Neurobiol. 19:275–283. 2009. View Article : Google Scholar : PubMed/NCBI
9	Dalva MB, Takasu MA, Lin MZ, Shamah SM, Hu L, Gale NW and Greenberg ME: EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell. 103:945–956. 2000. View Article : Google Scholar : PubMed/NCBI
10	Takasu MA, Dalva MB, Zigmond RE and Greenberg ME: Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science. 295:491–495. 2002. View Article : Google Scholar : PubMed/NCBI
11	Grunwald IC, Korte M, Adelmann G, Plueck A, Kullander K, Adams RH, Frotscher M, Bonhoeffer T and Klein R: Hippocampal plasticity requires postsynaptic ephrinBs. Nat Neurosci. 7:33–40. 2004. View Article : Google Scholar : PubMed/NCBI
12	Calò L, Spillantini M, Nicoletti F and Allen ND: Nurr1 co-localizes with EphB1 receptors in the developing ventral midbrain, and its expression is enhanced by the EphB1 ligand, ephrinB2. J Neurochem. 92:235–245. 2005. View Article : Google Scholar : PubMed/NCBI
13	Calò L, Cinque C, Patanè M, Schillaci D, Battaglia G, Melchiorri D, Nicoletti F and Bruno V: Interaction between ephrins/Eph receptors and excitatory amino acid receptors: Possible relevance in the regulation of synaptic plasticity and in the pathophysiology of neuronal degeneration. J Neurochem. 98:1–10. 2006. View Article : Google Scholar : PubMed/NCBI
14	Du J, Tran T, Fu C and Sretavan DW: Upregulation of EphB2 and ephrin-B2 at the optic nerve head of DBA/2J glaucomatous mice coincides with axon loss. Invest Ophthalmol Vis Sci. 48:5567–5581. 2007. View Article : Google Scholar : PubMed/NCBI
15	Fu CT, Tran T and Sretavan D: Axonal/glial upregulation of EphB/ephrin-B signaling in mouse experimental ocular hypertension. Invest Ophthalmol Vis Sci. 51:991–1001. 2010. View Article : Google Scholar : PubMed/NCBI
16	Dong LD, Gao F, Wang XH, Miao Y, Wang SY, Wu Y, Li F, Wu J, Cheng XL, Sun XH, et al: GluA2 trafficking is involved in apoptosis of retinal ganglion cells induced by activation of EphB/EphrinB reverse signaling in a rat chronic ocular hypertension model. J Neurosci. 35:5409–5421. 2015. View Article : Google Scholar : PubMed/NCBI
17	Sappington RM, Sidorova T, Long DJ and Calkins DJ: TRPV1: Contribution to retinal ganglion cell apoptosis and increased intracellular Ca²⁺ with exposure to hydrostatic pressure. Invest Ophthalmol Vis Sci. 50:717–728. 2009. View Article : Google Scholar : PubMed/NCBI
18	Ryskamp DA, Witkovsky P, Barabas P, Huang W, Koehler C, Akimov NP, Lee SH, Chauhan S, Xing W, Rentería RC, et al: The polymodal ion channel transient receptor potential vanilloid 4 modulates calcium flux, spiking rate, and apoptosis of mouse retinal ganglion cells. J Neurosci. 31:7089–7101. 2011. View Article : Google Scholar : PubMed/NCBI
19	Poornima V, Madhupriya M, Kootar S, Sujatha G, Kumar A and Bera AK: P2×7 receptor-pannexin 1 hemichannel association: Effect of extracellular calcium on membrane permeabilization. J Mol Neurosci. 46:585–594. 2012. View Article : Google Scholar : PubMed/NCBI
20	Bissig D, Goebel D and Berkowitz BA: Diminished vision in healthy aging is associated with increased retinal L-type voltage gated calcium channel ion influx. PLoS One. 8:e563402013. View Article : Google Scholar : PubMed/NCBI
21	Tomita G: The optic nerve head in normal-tension glaucoma. Curr Opin Ophthalmol. 11:116–120. 2000. View Article : Google Scholar : PubMed/NCBI
22	Wang SY, Singh K and Lin SC: The association between glaucoma prevalence and supplementation with the oxidants calcium and iron. Invest Ophthalmol Vis Sci. 53:725–731. 2012. View Article : Google Scholar : PubMed/NCBI
23	Chen J, Miao Y, Wang XH and Wang Z: Elevation of p-NR2A(S1232) by Cdk5/p35 contributes to retinal ganglion cell apoptosis in a rat experimental glaucoma model. Neurobiol Dis. 43:455–464. 2011. View Article : Google Scholar : PubMed/NCBI
24	Ji M, Miao Y, Dong LD, Chen J, Mo XF, Jiang SX, Sun XH, Yang XL and Wang Z: Group I mGluR-mediated inhibition of Kir channels contributes to retinal Müller cell gliosis in a rat chronic ocular hypertension model. J Neurosci. 32:12744–12755. 2012. View Article : Google Scholar : PubMed/NCBI
25	Yang W, Li Q, Wang SY, Gao F, Qian WJ, Li F, Ji M, Sun XH, Miao Y and Wang Z: Cannabinoid receptor agonists modulate calcium channels in rat retinal Müller cells. Neuroscience. 313:213–224. 2016. View Article : Google Scholar : PubMed/NCBI
26	Calò L, Bruno V, Spinsanti P, Molinari G, Korkhov V, Esposito Z, Patanè M, Melchiorri D, Freissmuth M and Nicoletti F: Interactions between ephrin-B and metabotropic glutamate 1 receptors in brain tissue and cultured neurons. J Neurosci. 25:2245–2254. 2005. View Article : Google Scholar : PubMed/NCBI
27	Hallett PJ and Standaert DG: Rationale for and use of NMDA receptor antagonists in Parkinson's disease. Pharmacol Ther. 102:155–174. 2004. View Article : Google Scholar : PubMed/NCBI
28	Surmeier DJ: Calcium ageing, and neuronal vulnerability in Parkinson's disease. Lancet Neurol. 6:933–938. 2007. View Article : Google Scholar : PubMed/NCBI
29	Fan MM and Raymond LA: N-methyl-D-aspartate (NMDA) receptor function and excitotoxicity in Huntington's disease. Prog Neurobiol. 81:272–293. 2007. View Article : Google Scholar : PubMed/NCBI
30	Bezprozvanny I: Inositol 1,4,5-tripshosphate receptor, calcium signalling and Huntington's disease. Subcell Biochem. 45:323–335. 2007. View Article : Google Scholar : PubMed/NCBI
31	Bezprozvanny I and Mattson MP: Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci. 31:454–463. 2008. View Article : Google Scholar : PubMed/NCBI
32	Green KN and LaFerla FM: Linking calcium to Abeta and Alzheimer's disease. Neuron. 59:190–194. 2008. View Article : Google Scholar : PubMed/NCBI
33	Delbono O, Garcia J, Appel SH and Stefani E: IgG from amyotrophic lateral sclerosis affects tubular calcium channels of skeletal muscle. Am J Physiol. 260:C1347–C1351. 1991.PubMed/NCBI
34	Arsac C, Raymond C, Martin-Moutot N, Dargent B, Couraud F, Pouget J and Seagar M: Immunoassays fail to detect antibodies against neuronal calcium channels in amyotrophic lateral sclerosis serum. Ann Neurol. 40:695–700. 1996. View Article : Google Scholar : PubMed/NCBI
35	Mayama C: Calcium channels and their blockers in intraocular pressure and glaucoma. Eur J Pharmacol. 739:96–105. 2014. View Article : Google Scholar : PubMed/NCBI
36	Hu XQ, Singh N, Mukhopadhyay D and Akbarali HI: Modulation of voltage-dependent Ca²⁺ channels in rabbit colonic smooth muscle cells by c-Src and focal adhesion kinase. J Biol Chem. 273:5337–5342. 1998. View Article : Google Scholar : PubMed/NCBI
37	Bence-Hanulec KK, Marshall J and Blair LA: Potentiation of neuronal L calcium channels by IGF-1 requires phosphorylation of the alpha1 subunit on a specific tyrosine residue. Neuron. 27:121–131. 2000. View Article : Google Scholar : PubMed/NCBI
38	Bogdelis A, Treinys R, Stankevičius E, Jurevičius J and Skeberdis VA: Src family protein tyrosine kinases modulate L-type calcium current in human atrial myocytes. Biochem Biophys Res Commun. 413:116–121. 2011. View Article : Google Scholar : PubMed/NCBI
39	Wang Y, Mishra R and Simonson MS: Ca²⁺/calmodulin-dependent protein kinase II stimulates c-fos transcription and DNA synthesis by a Src-based mechanism in glomerular mesangial cells. J Am Soc Nephrol. 14:28–36. 2003. View Article : Google Scholar : PubMed/NCBI
40	Pasek JG, Wang X and Colbran RJ: Differential CaMKII regulation by voltage-gated calcium channels in the striatum. Mol Cell Neurosci. 68:234–243. 2015. View Article : Google Scholar : PubMed/NCBI
41	Blesneac I, Chemin J, Bidaud I, Huc-Brandt S, Vandermoere F and Lory P: Phosphorylation of the Cav3.2 T-type calcium channel directly regulates its gating properties. Proc Natl Acad Sci USA. 112:pp. 13705–13710. 2015; View Article : Google Scholar : PubMed/NCBI