Activation of endogenously expressed ion channels by active complement in the retinal pigment epithelium

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• 作者：Andreas Genewsky ; Ingmar Jost…
• 关键词：(4-) ; complement system ; Retinal pigment epithelium ; RPE ; L ; type channels ; BK channels
• 刊名：Pfl篓鹿gers Archiv - European Journal of Physiology
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：467
• 期：10
• 页码：2179-2191
• 全文大小：1,134 KB
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• 作者单位：Andreas Genewsky (1) (2)
  Ingmar Jost (2)
  Catharina Busch (7)
  Christian Huber (7)
  Julia Stindl (2)
  Christine Skerka (3)
  Peter F. Zipfel (3) (4)
  B?rbel Rohrer (5) (6)
  Olaf Strau? (2) (7)
  
  1. Max-Planck Institute of Psychiatry, Munich, Germany
  2. Experimental Ophthalmology, Eye Clinic, University Medical Center Regensburg, Regensburg, Germany
  7. Experimental Ophthalmology, Department of Ophthalmology, Charite University Medicine Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany
  3. Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany
  4. Friedrich Schiller University, Jena, Germany
  5. Department of Ophthalmology, Medical University of South Carolina, Charleston, SC, 29425, USA
  6. Research Service, Ralph H. Johnson VA Medical Center, Charleston, SC, 29401, USA
  
• 刊物主题：Human Physiology;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-2013

文摘

Defective regulation of the alternative pathway of the complement system is believed to contribute to damage of retinal pigment epithelial (RPE) cells in age-related macular degeneration. Thus we investigated the effect of complement activation on the RPE cell membrane by analyzing changes in membrane conductance via patch-clamp techniques and Ca2+ imaging. Exposure of human ARPE-19 cells to complement-sufficient normal human serum (NHS) (25 %) resulted in a biphasic increase in intracellular free Ca2+ ([Ca2+]_i); an initial peak followed by sustained Ca2+ increase. C5- or C7-depleted sera did not fully reproduce the signal generated by NHS. The initial peak of the Ca2+ response was reduced by sarcoplasmic Ca2+-ATPase inhibitor thapsigargin, L-type channel blockers (R)-(+)-BayK8644 and isradipine, transient-receptor-potential (TRP) channel blocker ruthenium-red and ryanodine receptor blocker dantrolene. The sustained phase was carried by Ca_V1.3 L-type channels via tyrosine-phosphorylation. Changes in [Ca2+]_I were accompanied by an abrupt hyperpolarization, resulting from a transient increase in membrane conductance, which was absent under extracellular Ca2+- or K+-free conditions and blocked by (R)-(+)-BayK8644 or paxilline, a maxiK channel inhibitor. Single-channel recordings confirmed the contribution of maxiK channels. Primary porcine RPE cells responded to NHS in a comparable manner. Pre-incubation with NHS reduced H₂O₂-induced cell death. In summary, in a concerted manner, C3a, C5a and sC5b-9 increased [Ca2+]_i by ryanodine-receptor-dependent activation of L-type channels in addition to maxi-K channels and TRP channels absent from any insertion of a lytic pore. Keywords (4-): complement system Retinal pigment epithelium RPE L-type channels BK channels