May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Decreased Ca2+-Activated Cl- Secretion in Vmd2-/- Mice
Author Affiliations & Notes
  • R. Barro Soria
    Institut of Physiology, Univ Regensburg, Regensburg, Germany
  • R. Schreiber
    Institut of Physiology, Univ Regensburg, Regensburg, Germany
  • K. Kunzelmann
    Institut of Physiology, Univ Regensburg, Regensburg, Germany
  • Footnotes
    Commercial Relationships  R. Barro Soria, None; R. Schreiber, None; K. Kunzelmann, None.
  • Footnotes
    Support  Supported by DFG SFB699A7, Else-Kröner-Fresenius Stiftung and Friedrich Ebert Stiftung.
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 5179. doi:https://doi.org/
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      R. Barro Soria, R. Schreiber, K. Kunzelmann; Decreased Ca2+-Activated Cl- Secretion in Vmd2-/- Mice. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5179. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Bestrophin 1 (best1) is expressed in the retinal pigment epithelium (RPE) and has been proposed to be the Cl- channel that could control retinal homeostasis. Mutations in hbest1 cause an autosomal form of macular dystrophy (Best disease). However, it is not yet agreed that Best disease is caused by Cl- channel dysfunction. This is partly due to the fact that mbest1 knockout mice (vmd2-/-) show increased EOG signals indicating an increase in epithelial Cl- transport by the RPE. Moreover, best1 has also been proposed to function as a regulator of voltage-gated Ca2+ channels in the RPE. Best1 was also identified in other epithelial tissues, such as airways and colon where it enabled Ca2+ activated Cl- secretion.

Methods: : In order to get information on epithelial transport depending on bestrophins we used airway epithelia which is advantageous to measure trans-epithelial resistance in situ. We also performed patch clamp experiments in primary cultures of mouse tracheal epithelial cells (mTEC).

Results: : Purinergic agonists such as ATP produce larger short circuit current (Isc) in wild type (vmd2+/+) mouse tracheas compared to vmd2-/-. ATP-induced whole cell current in vmd2-/- mTEC was 21.75 ±; 2.92 nS whereas vmd2+/+ showed 42.01 ±; 7.2 nS. Short interfering RNA (RNAi) targeting mbest2 reduced ATP induced whole cell currents in vmd2-/- to 6.33 ±; 1.41 nS and to 25.83 ±; 5.23 nS in the vmd2+/+ mTEC. Additionally, suppression of best1 with RNAi reduced CaCIs in vmd2+/+ mTEC to 21.02 ±; 4.12 nS. ATP induced positive and negative whole cell currents in vmd2+/+ mTEC, but only half of that obtained in vmd2+/+. mTEC cells patch clamped with different intracellular free Ca2+ solutions showed also larger CaCI in vmd2+/+ than that obtained in vmd2-/-, but mainly in the positive direction. Analysis of the i/v curves further suggests that the lack of mbest1 in part hampers the Ca2+ influx impairing thereby a proper Cl- efflux.

Conclusions: : This is the first report of a phenotype in a non-ocular tissue in vmd2-/- mice. The clarification of the observed differences between airways and RPE will help to understand the specific behavior leading to Best disease.

Keywords: ion channels • electrophysiology: non-clinical 
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