| 2014 |
LRRC8D is required for import of the antibiotic blasticidin S into mammalian cells, demonstrating a transport function. LRRC8D localizes to the plasma membrane and physically interacts with LRRC8A, LRRC8B, and LRRC8C. |
Genetic screen/loss-of-function, co-immunoprecipitation, localization and topology assays |
The Journal of biological chemistry |
Medium |
24782309
|
| 2015 |
LRRC8D is a subunit of heteromeric volume-regulated anion channels (VRACs). LRRC8A/LRRC8D-containing VRACs mediate ~50% of cellular cisplatin/carboplatin uptake under isotonic conditions, and cell swelling strongly enhances this uptake. Incorporation of LRRC8D increases VRAC permeability for cisplatin and taurine relative to channels lacking LRRC8D, indicating LRRC8D contributes to pore properties. |
CRISPR/siRNA knockout, isotopic drug uptake assays, electrophysiology, genetic rescue |
The EMBO journal |
High |
26530471
|
| 2017 |
In primary rat astrocytes, LRRC8A/D-containing heteromeric VRACs preferentially mediate swelling-activated release of uncharged osmolytes (taurine, myo-inositol), whereas charged osmolyte (d-aspartate) release depends on LRRC8A/C/E-containing channels. LRRC8D knockdown strongly inhibits taurine and myo-inositol efflux without major effect on d-aspartate efflux, establishing subunit-specific substrate selectivity. |
RNAi knockdown, radiotracer flux assays with hypoosmotic challenge |
The Journal of physiology |
Medium |
28833202
|
| 2017 |
LRRC8A/D heteromeric channels are strongly inhibited by oxidation of intracellular cysteine residues (by chloramine-T or tert-butyl hydroperoxide), in contrast to LRRC8A/E heteromers which are potentiated. The extracellular loop domains (EL1, EL2) of LRRC8D contain external oxidation sites that confer susceptibility to oxidant-mediated inhibition. |
Electrophysiology of heterologously expressed fluorescently tagged LRRC8 heteromers, pharmacological oxidation, domain-swap chimeras |
The Journal of physiology |
Medium |
28841766 33932953
|
| 2018 |
Pancreatic islets prominently express LRRC8D alongside LRRC8A; LRRC8D-containing VRACs may mediate neurotransmitter-permeable channel activity in beta-cells, contributing to autocrine/paracrine signaling within islets. Loss of the essential subunit LRRC8A (which partners with LRRC8D) reduces first-phase glucose-induced insulin secretion and impairs glucose tolerance. |
Conditional knockout mice, patch-clamp electrophysiology, insulin secretion assays, glucose tolerance tests |
Nature communications |
Medium |
29773801
|
| 2018 |
The first extracellular loop (EL1) of LRRC8D (connecting transmembrane domains 1 and 2) is essential for VRAC activity. Chimeric channels in which EL1 of LRRC8A is replaced with that of LRRC8D confer functional VRAC activity and volume-dependent regulation. |
Chimeric channel mutagenesis, whole-cell patch clamp, hypotonicity-induced current recording |
The Journal of general physiology |
Medium |
29853476
|
| 2020 |
Cryo-EM structure of the human LRRC8D homo-hexamer reveals a two-fold symmetric arrangement. The extracellular pore constriction of LRRC8D is wider than in LRRC8A structures, explaining increased permeability for organic substrates. An N-terminal helix protrudes into the pore from the intracellular side and is implicated in gating. Structure-based electrophysiological mutagenesis confirmed these functional features. |
Cryo-EM structure determination, electrophysiology (structure-based mutagenesis) |
Communications biology |
High |
32415200
|
| 2020 |
LRRC8D inhibits cGAMP transport through VRAC. LRRC8A:C and LRRC8A:E heteromers transport cGAMP and other 2'3'-cyclic dinucleotides, whereas LRRC8D incorporation into the complex reduces this transport activity. |
CRISPR knockout screens, genetic rescue with individual subunits, cGAMP transport assays, STING pathway activation readout |
Molecular cell |
Medium |
33171122
|
| 2021 |
LRRC8D co-immunoprecipitates with NADPH oxidase 1 (Nox1) in vascular smooth muscle cells and co-localizes with Nox1 at the plasma membrane and in vesicles. LRRC8D knockdown potentiates NF-κB activation in response to TNFα, suggesting LRRC8D-containing VRACs negatively modulate this inflammatory signaling pathway. |
Co-immunoprecipitation, siRNA knockdown, NF-κB reporter assay, superoxide production assay |
The Journal of physiology |
Medium |
33932953
|
| 2022 |
LRRC8D localizes to basolateral membranes of proximal tubules in the kidney. Constitutive deletion of Lrrc8d in mice causes proximal tubular injury, increased diuresis, and mild Fanconi-like symptoms, establishing LRRC8A/D channels as required for basolateral exit of organic compounds including metabolites in proximal tubules. |
Epitope-tagged knock-in mice for localization, constitutive Lrrc8d knockout mice, histology, urine/serum metabolomics |
Journal of the American Society of Nephrology : JASN |
High |
35777784
|
| 2022 |
Loss of LRRC8D significantly reduces cis- and carboplatin uptake in BRCA1;p53-deficient mouse mammary tumor cells, resulting in reduced DNA damage and in vivo drug resistance. Lrrc8d deletion in mice does not affect viability or fertility, unlike Lrrc8a deletion. |
Conditional/constitutive gene knockout in mice, platinum drug uptake measurement, DNA damage assays, in vivo tumor treatment |
Cancer research communications |
Medium |
36467895
|
| 2024 |
In the cochlea, LRRC8D is expressed in sensory hair cells and in the stria vascularis (alongside LRRC8A and LRRC8E). Combined ablation of LRRC8D and LRRC8E results in cochlear degeneration and congenital deafness, with severe reduction in the endocochlear potential and loss of Kir4.1 (KCNJ10) expression, suggesting LRRC8D-containing VRACs transport metabolites (e.g., glutathione) needed to maintain inner ear redox potential. |
Conditional knockout mice, auditory brainstem response, endocochlear potential measurement, immunohistochemistry, Western blot |
The Journal of biological chemistry |
Medium |
38838775
|
| 2025 |
NAA60, an N-terminal acetyltransferase localized to the Golgi apparatus, acetylates the N-termini of LRRC8A and LRRC8D. Loss of NAA60 decreases cis- and carboplatin uptake; introduction of positively charged amino acids at the LRRC8A/D N-termini (mimicking absence of acetylation) similarly decreases platinum drug sensitivity, establishing N-terminal acetylation as a post-translational modification required for LRRC8A/D-mediated drug uptake. |
Co-immunoprecipitation/mass spectrometry, N-terminal acetylation assays, site-directed mutagenesis (charge substitution), drug uptake assays, in vivo tumor models |
Communications biology |
Medium |
41053424
|
| 2024 |
Cryo-EM structures of a native-like LRRC8A:D VRAC with 4:2 stoichiometry reveal that LRRC8D subunits increase hydrophobicity and widen the selectivity filter compared to LRRC8A homomers, explaining LRRC8D-unique substrate selectivity. Lipids occupy the pore in the closed state (as in LRRC8A:C VRACs). Incorporation of LRRC8D disrupts packing of cytoplasmic LRR domains, increases channel dynamics, and opens lateral fenestrations proposed to be necessary for pore lipid evacuation and channel activation. Electrophysiology confirmed lipid-gating is a general VRAC property. |
Cryo-EM structure determination (4:2 stoichiometry), electrophysiology |
bioRxivpreprint |
Medium |
bio_10.1101_2024.11.24.625074
|
| 2025 |
In lateral ventricular neural stem cells, LRRC8D (a core VRAC component) participates in GABA transport/signaling and provides negative feedback to ChAT+ neurons in the ACC-subependymal circuit, with evidence that LRRC8D-regulated chloride and GABA transport modulates neural stem cell proliferation. |
Immunohistochemistry, in vivo circuit activation, functional behavioral/proliferation readouts |
Cells |
Low |
40136675
|