缝隙连接在视网膜中的生理功能和视网膜疾病中的作用_Chinese Journal of Ocular Fundus Diseases

Authors：

于广委 , 张琰 , 王红星 ,  李筱荣

300384 天津医科大学眼科医院天津医科大学眼科研究所天津医科大学眼视光学院;

Corresponding author：

李筱荣, Email: xiaorli@163.com

Keywords：

连接蛋白类; 视网膜/生理学; 视网膜疾病/病理生理学; 综述

DOI：

10.3760/cma.j.issn.1005-1015.2014.04.028

Video：

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缝隙连接是相邻细胞之间直接交换离子和小分子物质的通道, 由相邻细胞膜上的2个连接子相互锚定组成。连接子是由6个缝隙连接蛋白亚单位构成的六聚体。视网膜各层细胞均有缝隙连接蛋白表达。缝隙连接不仅参与视网膜发育过程的调控, 协助和增强视觉信息的传递以及维持神经元细胞外微环境的稳态; 也和糖尿病视网膜病变、青光眼、老年性黄斑变性、视网膜色素变性以及视网膜损伤等视网膜疾病的发生发展密切相关。以缝隙连接为靶点干预治疗视网膜疾病将逐渐成为国内外眼底疾病研究的热点。

Citation： 于广委, 张琰, 王红星, 李筱荣. 缝隙连接在视网膜中的生理功能和视网膜疾病中的作用. Chinese Journal of Ocular Fundus Diseases, 2014, 30(4): 425-428. doi: 10.3760/cma.j.issn.1005-1015.2014.04.028 Copy

1.	Volgyi B, Kovacs-Oller T, Atlasz T, et al. Gap junctional coupling in the vertebrate retina: variations on one theme?[J]. Prog Retin Eye Res, 2013, 34: 1-18.
2.	Roy S, Trudeau K, Roy S, et al. New insights into hyperglycemia-induced molecular changes in microvascular cells[J]. J Dent Res, 2010, 89: 116-127.
3.	Kerr NM, Johnson CS, Green CR, et al. Gap junction protein connexin43(GJA1) in the human glaucomatous optic nerve head and retina[J]. J Clin Neurosci, 2011, 18: 102-108.
4.	Pocrnich CE, Shao Q, Liu H, et al. The effect of connexin43 on the level of vascular endothelial growth factor in human retinal pigment epithelial cells[J]. Graefe's Arch Clin Exp Ophthalmol, 2012, 250: 515-522.
5.	Ripps H. Cell death in retinitis pigmentosa: gap junctions and the 'bystander' effect[J]. Exp Eye Res, 2002, 74: 327-336.
6.	Oshima A. Structure and closure of connexin gap junction channels[J]. FEBS Lett, 2014, 588: 1230-1237.
7.	Laird DW. Life cycle of connexins in health and disease[J]. Biochem J, 2006, 394: 527-543.
8.	Dere E, Zlomuzica A. The role of gap junctions in the brain in health and disease[J]. Neurosci Biobehav Rev, 2012, 36: 206-217.
9.	Peixoto PM, Ryu SY, Pruzansky DP, et al. Mitochondrial apoptosis is amplified through gap junctions[J]. Biochem Biophys Res Commun, 2009, 390: 38-43.
10.	Wang Y, Song JH, Denisova JV, et al. Neuronal gap junction coupling is regulated by glutamate and plays critical role in cell death during neuronal injury[J]. J Neurosci, 2012, 32: 713-725.
11.	Kar R, Batra N, Riquelme MA, et al. Biological role of connexin intercellular channels and hemichannels[J]. Arch Biochem Biophys, 2012, 524: 2-15.
12.	Sohl G, Maxeiner S, Willecke K. Expression and functions of neuronal gap junctions[J]. Nat Rev Neurosci, 2005, 6: 191-200.
13.	Kihara AH, Santos TO, Osuna-Melo EJ, et al. Connexin-mediated communication controls cell proliferation and is essential in retinal histogenesis[J]. Int J Dev Neurosci, 2010, 28: 39-52.
14.	O'Brien JJ, Chen X, Macleish PR, et al. Photoreceptor coupling mediated by connexin36 in the primate retina[J]. J Neurosci, 2012, 32: 4675-4687.
15.	Feigenspan A, Teubner B, Willecke K, et al. Expression of neuronal connexin36 in AⅡ amacrine cells of the mammalian retina[J]. J Neurosci, 2001, 21: 230-239.
16.	Feigenspan A, Janssen-Bienhold U, Hormuzdi S, et al. Expression of connexin36 in cone pedicles and OFF-cone bipolar cells of the mouse retina[J]. J Neurosci, 2004, 24: 3325-3234.
17.	Pan F, Paul DL, Bloomfield SA, et al. Connexin36 is required for gap junctional coupling of most ganglion cell subtypes in the mouse retina[J]. J Comp Neurol, 2010, 518: 911-927.
18.	Johansson K, Bruun A, Ehinger B. Gap junction protein connexin43 is heterogeneously expressed among glial cells in the adult rabbit retina[J]. J Comp Neurol, 1999, 407: 395-403.
19.	Guldenagel M, Sohl G, Plum A, et al. Expression patterns of connexin genes in mouse retina[J]. J Comp Neurol, 2000, 425: 193-201.
20.	Kerr NM, Johnson CS, de Souza CF, et al. Immunolocalization of gap junction protein connexin43(GJA1) in the human retina and optic nerve[J]. Invest Ophthalmol Vis Sci, 2010, 51: 4028-4034.
21.	Hilgen G, von MJ, Willecke K, et al. Subcellular distribution of connexin45 in OFF bipolar cells of the mouse retina[J]. J Comp Neurol, 2011, 519: 433-450.
22.	Maxeiner S, Dedek K, Janssen-Bienhold U, et al. Deletion of connexin45 in mouse retinal neurons disrupts the rod/cone signaling pathway between AⅡ amacrine and ON cone bipolar cells and leads to impaired visual transmission[J]. J Neurosci, 2005, 25: 566-576.
23.	Palacios-Prado N, Sonntag S, Skeberdis VA, et al. Gating, permselectivity and pH-dependent modulation of channels formed by connexin57, a major connexin of horizontal cells in the mouse retina[J]. J Physiol, 2009, 587: 3251-3269.
24.	Pan F, Keung J, Kim IB, et al. Connexin 57 is expressed by the axon terminal network of B-type horizontal cells in the rabbit retina[J]. J Comp Neurol, 2012, 520: 2256-2274.
25.	Zhang Y, Semple-Rowland SL. Rhythmic expression of clock-controlled genes in retinal photoreceptors is sensitive to 18-beta-glycyrrhetnic acid and 18-alpha-glycyrrhetnic acid-3-hemisuccinate[J]. Brain Res Mol Brain Res, 2005, 135: 30-39.
26.	Cook JE, Becker DL. Gap-junction proteins in retinal development: new roles for the ""nexus""[J]. Physiology (Bethesda), 2009, 24: 219-230.
27.	Deans MR, Volgyi B, Goodenough DA, et al. Connexin36 is essential for transmission of rod-mediated visual signals in the mammalian retina[J]. Neuron, 2002, 36: 703-712.
28.	Demb JB, Pugh EN. Connexin36 forms synapses essential for night vision[J]. Neuron, 2002, 36: 551-553.
29.	Cronin M, Anderson PN, Cook JE, et al. Blocking connexin43 expression reduces inflammation and improves functional recovery after spinal cord injury[J]. Mol Cell Neurosci, 2008, 39: 152-160.
30.	Schubert T, Maxeiner S, Kruger O, et al. Connexin45 mediates gap junctional coupling of bistratified ganglion cells in the mouse retina[J]. J Comp Neurol, 2005, 490: 29-39.
31.	Sonntag S, Dedek K, Dorgau B, et al. Ablation of retinal horizontal cells from adult mice leads to rod degeneration and remodeling in the outer retina[J]. J Neurosci, 2012, 32: 10713-10724.
32.	Shelley J, Dedek K, Schubert T, et al. Horizontal cell receptive fields are reduced in connexin57-deficient mice[J]. Eur J Neurosci, 2006, 23: 3176-3186.
33.	Sato T, Haimovici R, Kao R, et al. Downregulation of connexin 43 expression by high glucose reduces gap junction activity in microvascular endothelial cells[J]. Diabetes, 2002, 51: 1565-1571.
34.	Fernandes R, Girao H, Pereira P. High glucose down-regulates intercellular communication in retinal endothelial cells by enhancing degradation of connexin 43 by a proteasome-dependent mechanism[J]. J Biol Chem, 2004, 279: 27219-27224.
35.	Trudeau K, Muto T, Roy S. Downregulation of mitochondrial connexin 43 by high glucose triggers mitochondrial shape change and cytochrome C release in retinal endothelial cells[J]. Invest Ophthalmol Vis Sci, 2012, 53: 6675-6681.
36.	Manasson J, Tien T, Moore C, et al. High glucose-induced downregulation of connexin 30.2 promotes retinal vascular lesions: implications for diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2013, 54: 2361-2366.
37.	Shibata M, Oku H, Sugiyama T, et al. Disruption of gap junctions may be involved in impairment of autoregulation in optic nerve head blood flow of diabetic rabbits[J]. Invest Ophthalmol Vis Sci, 2011, 52: 2153-2159.
38.	Malone P, Miao H, Parker A, et al. Pressure induces loss of gap junction communication and redistribution of connexin 43 in astrocytes[J]. Glia, 2007, 55: 1085-1098.
39.	Bringmann A, Wiedemann P. Muller glial cells in retinal disease[J]. Ophthalmologica, 2012, 227: 1-19.
40.	Deva NC, Zhang J, Green CR, et al. Connexin43 modulation inhibits scarring in a rabbit eye glaucoma trabeculectomy model[J]. Inflammation, 2012, 35: 1276-1286.
41.	Wittig D, Wang X, Walter C, et al. Multi-level communication of human retinal pigment epithelial cells via tunneling nanotubes[J/OL]. PLoS One, 2012, 7: 33195[2012-03-22]. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0033195.
42.	Pocrnich CE, Shao Q, Liu H, et al. The effect of connexin43 on the level of vascular endothelial growth factor in human retinal pigment epithelial cells[J]. Graefe's Arch Clin Exp Ophthalmol, 2012, 250: 515-522.
43.	Cusato K, Bosco A, Rozental R, et al. Gap junctions mediate bystander cell death in developing retina[J]. J Neurosci, 2003, 23: 6413-6422.
44.	Kranz K, Paquet-Durand F, Weiler R, et al. Testing for a gap junction-mediated bystander effect in retinitis pigmentosa: secondary cone death is not altered by deletion of connexin36 from cones[J/OL]. PLoS One, 2013, 8: 57163[2013-02-27]. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0057163.
45.	Paschon V, Higa GS, Resende RR, et al. Blocking of connexin-mediated communication promotes neuroprotection during acute degeneration induced by mechanical trauma[J/OL]. PLoS One, 2012, 7: 45449[2012-09-20]. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045449.
46.	Striedinger K, Petrasch-Parwez E, Zoidl G, et al. Loss of connexin36 increases retinal cell vulnerability to secondary cell loss[J]. Eur J Neurosci, 2005, 22: 605-616.
47.	Kerr NM, Johnson CS, Zhang J, et al. High pressure-induced retinal ischaemia reperfusion causes upregulation of gap junction protein connexin43 prior to retinal ganglion cell loss[J]. Exp Neurol, 2012, 234: 144-152.
48.	Danesh-Meyer HV, Kerr NM, Zhang J, et al. Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia[J]. Brain, 2012, 135: 506-520.

1. Volgyi B, Kovacs-Oller T, Atlasz T, et al. Gap junctional coupling in the vertebrate retina: variations on one theme?[J]. Prog Retin Eye Res, 2013, 34: 1-18.
2. Roy S, Trudeau K, Roy S, et al. New insights into hyperglycemia-induced molecular changes in microvascular cells[J]. J Dent Res, 2010, 89: 116-127.
3. Kerr NM, Johnson CS, Green CR, et al. Gap junction protein connexin43(GJA1) in the human glaucomatous optic nerve head and retina[J]. J Clin Neurosci, 2011, 18: 102-108.
4. Pocrnich CE, Shao Q, Liu H, et al. The effect of connexin43 on the level of vascular endothelial growth factor in human retinal pigment epithelial cells[J]. Graefe's Arch Clin Exp Ophthalmol, 2012, 250: 515-522.
5. Ripps H. Cell death in retinitis pigmentosa: gap junctions and the 'bystander' effect[J]. Exp Eye Res, 2002, 74: 327-336.
6. Oshima A. Structure and closure of connexin gap junction channels[J]. FEBS Lett, 2014, 588: 1230-1237.
7. Laird DW. Life cycle of connexins in health and disease[J]. Biochem J, 2006, 394: 527-543.
8. Dere E, Zlomuzica A. The role of gap junctions in the brain in health and disease[J]. Neurosci Biobehav Rev, 2012, 36: 206-217.
9. Peixoto PM, Ryu SY, Pruzansky DP, et al. Mitochondrial apoptosis is amplified through gap junctions[J]. Biochem Biophys Res Commun, 2009, 390: 38-43.
10. Wang Y, Song JH, Denisova JV, et al. Neuronal gap junction coupling is regulated by glutamate and plays critical role in cell death during neuronal injury[J]. J Neurosci, 2012, 32: 713-725.
11. Kar R, Batra N, Riquelme MA, et al. Biological role of connexin intercellular channels and hemichannels[J]. Arch Biochem Biophys, 2012, 524: 2-15.
12. Sohl G, Maxeiner S, Willecke K. Expression and functions of neuronal gap junctions[J]. Nat Rev Neurosci, 2005, 6: 191-200.
13. Kihara AH, Santos TO, Osuna-Melo EJ, et al. Connexin-mediated communication controls cell proliferation and is essential in retinal histogenesis[J]. Int J Dev Neurosci, 2010, 28: 39-52.
14. O'Brien JJ, Chen X, Macleish PR, et al. Photoreceptor coupling mediated by connexin36 in the primate retina[J]. J Neurosci, 2012, 32: 4675-4687.
15. Feigenspan A, Teubner B, Willecke K, et al. Expression of neuronal connexin36 in AⅡ amacrine cells of the mammalian retina[J]. J Neurosci, 2001, 21: 230-239.
16. Feigenspan A, Janssen-Bienhold U, Hormuzdi S, et al. Expression of connexin36 in cone pedicles and OFF-cone bipolar cells of the mouse retina[J]. J Neurosci, 2004, 24: 3325-3234.
17. Pan F, Paul DL, Bloomfield SA, et al. Connexin36 is required for gap junctional coupling of most ganglion cell subtypes in the mouse retina[J]. J Comp Neurol, 2010, 518: 911-927.
18. Johansson K, Bruun A, Ehinger B. Gap junction protein connexin43 is heterogeneously expressed among glial cells in the adult rabbit retina[J]. J Comp Neurol, 1999, 407: 395-403.
19. Guldenagel M, Sohl G, Plum A, et al. Expression patterns of connexin genes in mouse retina[J]. J Comp Neurol, 2000, 425: 193-201.
20. Kerr NM, Johnson CS, de Souza CF, et al. Immunolocalization of gap junction protein connexin43(GJA1) in the human retina and optic nerve[J]. Invest Ophthalmol Vis Sci, 2010, 51: 4028-4034.
21. Hilgen G, von MJ, Willecke K, et al. Subcellular distribution of connexin45 in OFF bipolar cells of the mouse retina[J]. J Comp Neurol, 2011, 519: 433-450.
22. Maxeiner S, Dedek K, Janssen-Bienhold U, et al. Deletion of connexin45 in mouse retinal neurons disrupts the rod/cone signaling pathway between AⅡ amacrine and ON cone bipolar cells and leads to impaired visual transmission[J]. J Neurosci, 2005, 25: 566-576.
23. Palacios-Prado N, Sonntag S, Skeberdis VA, et al. Gating, permselectivity and pH-dependent modulation of channels formed by connexin57, a major connexin of horizontal cells in the mouse retina[J]. J Physiol, 2009, 587: 3251-3269.
24. Pan F, Keung J, Kim IB, et al. Connexin 57 is expressed by the axon terminal network of B-type horizontal cells in the rabbit retina[J]. J Comp Neurol, 2012, 520: 2256-2274.
25. Zhang Y, Semple-Rowland SL. Rhythmic expression of clock-controlled genes in retinal photoreceptors is sensitive to 18-beta-glycyrrhetnic acid and 18-alpha-glycyrrhetnic acid-3-hemisuccinate[J]. Brain Res Mol Brain Res, 2005, 135: 30-39.
26. Cook JE, Becker DL. Gap-junction proteins in retinal development: new roles for the ""nexus""[J]. Physiology (Bethesda), 2009, 24: 219-230.
27. Deans MR, Volgyi B, Goodenough DA, et al. Connexin36 is essential for transmission of rod-mediated visual signals in the mammalian retina[J]. Neuron, 2002, 36: 703-712.
28. Demb JB, Pugh EN. Connexin36 forms synapses essential for night vision[J]. Neuron, 2002, 36: 551-553.
29. Cronin M, Anderson PN, Cook JE, et al. Blocking connexin43 expression reduces inflammation and improves functional recovery after spinal cord injury[J]. Mol Cell Neurosci, 2008, 39: 152-160.
30. Schubert T, Maxeiner S, Kruger O, et al. Connexin45 mediates gap junctional coupling of bistratified ganglion cells in the mouse retina[J]. J Comp Neurol, 2005, 490: 29-39.
31. Sonntag S, Dedek K, Dorgau B, et al. Ablation of retinal horizontal cells from adult mice leads to rod degeneration and remodeling in the outer retina[J]. J Neurosci, 2012, 32: 10713-10724.
32. Shelley J, Dedek K, Schubert T, et al. Horizontal cell receptive fields are reduced in connexin57-deficient mice[J]. Eur J Neurosci, 2006, 23: 3176-3186.
33. Sato T, Haimovici R, Kao R, et al. Downregulation of connexin 43 expression by high glucose reduces gap junction activity in microvascular endothelial cells[J]. Diabetes, 2002, 51: 1565-1571.
34. Fernandes R, Girao H, Pereira P. High glucose down-regulates intercellular communication in retinal endothelial cells by enhancing degradation of connexin 43 by a proteasome-dependent mechanism[J]. J Biol Chem, 2004, 279: 27219-27224.
35. Trudeau K, Muto T, Roy S. Downregulation of mitochondrial connexin 43 by high glucose triggers mitochondrial shape change and cytochrome C release in retinal endothelial cells[J]. Invest Ophthalmol Vis Sci, 2012, 53: 6675-6681.
36. Manasson J, Tien T, Moore C, et al. High glucose-induced downregulation of connexin 30.2 promotes retinal vascular lesions: implications for diabetic retinopathy[J]. Invest Ophthalmol Vis Sci, 2013, 54: 2361-2366.
37. Shibata M, Oku H, Sugiyama T, et al. Disruption of gap junctions may be involved in impairment of autoregulation in optic nerve head blood flow of diabetic rabbits[J]. Invest Ophthalmol Vis Sci, 2011, 52: 2153-2159.
38. Malone P, Miao H, Parker A, et al. Pressure induces loss of gap junction communication and redistribution of connexin 43 in astrocytes[J]. Glia, 2007, 55: 1085-1098.
39. Bringmann A, Wiedemann P. Muller glial cells in retinal disease[J]. Ophthalmologica, 2012, 227: 1-19.
40. Deva NC, Zhang J, Green CR, et al. Connexin43 modulation inhibits scarring in a rabbit eye glaucoma trabeculectomy model[J]. Inflammation, 2012, 35: 1276-1286.
41. Wittig D, Wang X, Walter C, et al. Multi-level communication of human retinal pigment epithelial cells via tunneling nanotubes[J/OL]. PLoS One, 2012, 7: 33195[2012-03-22]. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0033195.
42. Pocrnich CE, Shao Q, Liu H, et al. The effect of connexin43 on the level of vascular endothelial growth factor in human retinal pigment epithelial cells[J]. Graefe's Arch Clin Exp Ophthalmol, 2012, 250: 515-522.
43. Cusato K, Bosco A, Rozental R, et al. Gap junctions mediate bystander cell death in developing retina[J]. J Neurosci, 2003, 23: 6413-6422.
44. Kranz K, Paquet-Durand F, Weiler R, et al. Testing for a gap junction-mediated bystander effect in retinitis pigmentosa: secondary cone death is not altered by deletion of connexin36 from cones[J/OL]. PLoS One, 2013, 8: 57163[2013-02-27]. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0057163.
45. Paschon V, Higa GS, Resende RR, et al. Blocking of connexin-mediated communication promotes neuroprotection during acute degeneration induced by mechanical trauma[J/OL]. PLoS One, 2012, 7: 45449[2012-09-20]. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0045449.
46. Striedinger K, Petrasch-Parwez E, Zoidl G, et al. Loss of connexin36 increases retinal cell vulnerability to secondary cell loss[J]. Eur J Neurosci, 2005, 22: 605-616.
47. Kerr NM, Johnson CS, Zhang J, et al. High pressure-induced retinal ischaemia reperfusion causes upregulation of gap junction protein connexin43 prior to retinal ganglion cell loss[J]. Exp Neurol, 2012, 234: 144-152.
48. Danesh-Meyer HV, Kerr NM, Zhang J, et al. Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia[J]. Brain, 2012, 135: 506-520.

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缝隙连接在视网膜中的生理功能和视网膜疾病中的作用

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