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LRRC8A is essential for swelling-activated chloride current and for regulatory volume decrease in astrocytes.

Francesco Formaggio1,2, Emanuela Saracino3, Maria Grazia Mola4

  • 1Laboratory of Human and General Physiology, Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|June 30, 2018
PubMed
Summary
This summary is machine-generated.

Leucine-rich repeat-containing 8A (LRRC8A) is crucial for astrocyte cell volume regulation. This study shows LRRC8A is essential for swelling-activated chloride currents and volume recovery in astrocytes.

Keywords:
VRACcentral nervous systemedemaion channelsvolume regulation

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Physiology

Background:

  • Astroglial cells regulate cellular volume via ion channels and aquaporin-4.
  • Volume-regulated anion channels (VRACs) are critical for astrocyte volume regulation, activated by cell swelling.
  • The leucine-rich repeat-containing 8 (LRRC8) protein family is the identified molecular basis for VRACs.

Purpose of the Study:

  • To investigate the role of LRRC8A in astrocytic volume regulation.
  • To confirm LRRC8A as the molecular underpinning of VRAC currents in astrocytes.
  • To provide direct evidence for LRRC8A's function in astrocytic regulatory volume decrease.

Main Methods:

  • RNA interference targeting LRRC8A in primary cortical astrocytes.
  • Patch-clamp electrophysiology to measure VRAC currents.
  • Water-permeability assays and cell volume measurements.
  • Immunoblotting, immunofluorescence, confocal microscopy, and immunogold electron microscopy.

Main Results:

  • LRRC8A knockdown abolished swelling-activated chloride currents (VRAC) in astrocytes.
  • Loss of LRRC8A prevented cell volume recovery after hypotonic challenge.
  • LRRC8A was localized to the plasma membrane of astrocytes, including at the perivascular interface.

Conclusions:

  • LRRC8A is an essential subunit of VRAC in astrocytes.
  • LRRC8A plays a critical role in maintaining astroglial volume homeostasis.
  • This study provides direct evidence for LRRC8A's function in astrocytic regulatory volume decrease.