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Volume- and acid-sensitive outwardly rectifying anion channels (VSOR and ASOR) activated by swelling and acidification exhibit voltage-dependent inactivation and activation time courses, respectively. Recently, LRRC8A and some paralogs were shown to be essentially involved in the activity and inactivation kinetics of VSOR currents in human colonic HCT116 cells. In human cervix HeLa cells, here, inactivation of VSOR currents was found to become accelerated by RNA silencing only of LRRC8A but never decelerated by that of any LRRC8 isoform. These data suggest that LRRC8A is associated with the deceleration mechanism of VSOR inactivation, while none of LRRC8 members is related to the acceleration mechanism. Activation kinetics of ASOR currents was unaffected by knockdown of any LRRC8 family member. Double, triple and quadruple gene-silencing studies indicated that combinatory expression of LRRC8A with LRRC8D and LRRC8C is essential for VSOR activity, whereas none of LRRC8 family members is involved in ASOR activity.
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http://dx.doi.org/10.1080/19336950.2016.1230574 | DOI Listing |
EMBO J
January 2025
Division of Genetic Medicine, Lausanne University Hospital (CHUV), and University of Lausanne, 1011, Lausanne, Switzerland.
Volume-regulated anion channels (VRACs) are multimeric proteins composed of different paralogs of the LRRC8 family. They are activated in response to hypotonic swelling, but little is known about their specific functions. We studied two human individuals with the same congenital syndrome affecting blood vessels, brain, eyes, and bones.
View Article and Find Full Text PDFNat Commun
March 2023
Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO, USA.
The pannexin 2 channel (PANX2) participates in multiple physiological processes including skin homeostasis, neuronal development, and ischemia-induced brain injury. However, the molecular basis of PANX2 channel function remains largely unknown. Here, we present a cryo-electron microscopy structure of human PANX2, which reveals pore properties contrasting with those of the intensely studied paralog PANX1.
View Article and Find Full Text PDFAm J Physiol Cell Physiol
March 2021
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee.
Swelling-activated volume-regulated anion channels (VRACs) are heteromeric channels comprising LRRC8A and at least one other LRRC8 paralog. Cryoelectron microscopy (cryo-EM) structures of nonnative LRRC8A and LRRC8D homohexamers have been described. We demonstrate here that LRRC8A homohexamers poorly recapitulate VRAC functional properties.
View Article and Find Full Text PDFBiol Open
January 2020
Department of Animal Science and Technology, National Taiwan University, Taipei, 106, Taiwan
The sodium osmotic gradient is necessary for the initiation of brain ventricle inflation, but a previous study predicted that organic and inorganic osmolytes play equivalently important roles in osmotic homeostasis in astrocytes. To test whether organic osmoregulation also plays a role in brain ventricle inflation, the core component for volume-regulated anion and organic osmolyte channel, , was investigated in the zebrafish model. RT-PCR and whole-mount hybridization indicated that both genes were ubiquitously expressed through to 12 hpf, and around the ventricular layer of neural tubes and the cardiogenic region at 24 hpf.
View Article and Find Full Text PDFBiophys J
April 2019
Freie Universität Berlin, Institute of Chemistry and Biochemistry, Berlin, Germany. Electronic address:
Volume-regulated anion channels (VRACs) are key players in regulatory volume decrease of vertebrate cells by mediating the extrusion of chloride and organic osmolytes. They play additional roles in various physiological processes beyond their role in osmotic volume regulation. VRACs are formed by heteromers of LRRC8 proteins; LRRC8A (also called SWELL1) is an essential subunit that combines with any of its paralogs, LRRC8B-E, to form hexameric VRAC complexes.
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