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Review
. 2019 Apr 2;116(7):1185-1193.
doi: 10.1016/j.bpj.2019.02.014. Epub 2019 Feb 26.

Biophysics and Structure-Function Relationships of LRRC8-Formed Volume-Regulated Anion Channels

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Free PMC article
Review

Biophysics and Structure-Function Relationships of LRRC8-Formed Volume-Regulated Anion Channels

Benjamin König et al. Biophys J. .
Free PMC article

Abstract

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. The subunit composition of VRACs determines electrophysiological characteristics of their anion transport such as single-channel conductance, outward rectification, and depolarization-dependent inactivation kinetics. In addition, differently composed VRACs conduct diverse substrates, such as LRRC8D enhancing VRAC permeability to organic substances like taurine or cisplatin. Here, after a recapitulation of the biophysical properties of VRAC-mediated ion and osmolyte transport, we summarize the insights gathered since the molecular identification of VRACs. We describe the recently solved structures of LRRC8 complexes and discuss them in terms of their structure-function relationships. These studies open up many potential avenues for future research.

Figures

Figure 1
Figure 1
VRAC-mediated currents. (A) Current traces (dotted line indicates zero current) of hypotonicity-activated VRAC currents by native VRAC in human embryo kidney cells are shown, measured in 20-mV steps between −120 and 120 mV, showing outward rectification and voltage-dependent inactivation at positive potentials. From (4). (B) Single-channel currents at indicated voltages from Xenopus oocytes expressing fluorescently tagged LRRC8A and LRRC8E are shown. From (28).
Figure 2
Figure 2
Structure of LRRC8 complexes. (A) A schematic representation of the predicted LRRC8 protein topology (58) (left) and of the structure of a single LRRC8 subunit in an LRRC8 hexamer (30, 31, 32, 33) (right) is shown. (B) Ribbon representation of an LRRC8A subunit from a hexamer (Protein Data Bank [PDB]: 6DJB, (32)) is shown. Structural features are illustrated using the same color code as in (A). EL1H, TMH1, TMH2, IL1H1, and IL1H3 face the channel pore to the left of the subunit. Only a short carboxy-terminal portion of the NTC is resolved. Unresolved stretches connecting EL1β with EL1H and IL1H2 with IL1H3 are depicted as dashed lines. (C) Structures of an LRRC8A hexamer (PDB: 5ZSU, (31)) are shown, viewed parallel to the membrane with two subunits in the back not shown for clarity (left) and from the intracellular side (right), with individual subunits distinguished by different colors. Note the C3 symmetry (trimer of dimers) of the LRRD. (D) Pore radius along the symmetry axis is shown with the position of key amino acids depicted. The unresolved NTC may reach into the dilation. To see this figure in color, go online.

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