Affinage

LRRC26

Leucine-rich repeat-containing protein 26 · UniProt Q2I0M4

Length
334 aa
Mass
34.9 kDa
Annotated
2026-06-10
11 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRRC26 is the prototypical auxiliary γ1 subunit of large-conductance Ca²⁺- and voltage-activated BK (BKα) channels, conferring channel activation at physiological resting potentials without elevated cytosolic Ca²⁺ by producing a ~140 mV leftward shift in voltage-dependent activation (PMID:20613726). Mechanistically, LRRC26 acts on the channel-opening reaction itself: it increases the closed-open equilibrium constant ~10⁶-fold at zero mV by destabilizing the closed state and enhancing voltage-sensor–pore coupling, without altering voltage-sensor movement per se (PMID:41701845), and a single γ1 subunit per BKα tetramer is sufficient for the full all-or-none gating shift (PMID:41784352). This modulation also reshapes BK pharmacology, strongly suppressing mallotoxin efficacy (PMID:21984254). Physiologically, LRRC26 co-assembles with surface BKα in secretory epithelia and smooth muscle, where its loss reverts gating toward α-only behavior: in vascular and bronchial smooth muscle it sets BK voltage and Ca²⁺ sensitivity and limits myogenic tone (PMID:24906643, PMID:31800260), and in secretory epithelial cells (lacrimal, parotid, colonic goblet cells) it is required for BK-dependent K⁺ secretion, transepithelial K⁺ transport, and protection against DSS-induced colitis (PMID:28416688, PMID:33431687). Beyond its channel role, LRRC26 negatively regulates NF-κB signaling in triple-negative breast cancer cells, where its methylation-associated silencing de-represses inflammatory target genes and promotes invasion and migration (PMID:29512727).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2010 High

    Established that LRRC26 is a BK channel auxiliary protein, answering how BK channels can open at resting voltage without high Ca²⁺ by enhancing allosteric voltage-sensor/gate coupling.

    Evidence Patch-clamp electrophysiology of BKα–LRRC26 complexes in LNCaP cells and heterologous expression

    PMID:20613726

    Open questions at the time
    • Did not resolve whether the shift arises from altered voltage-sensor movement vs. the opening reaction
    • Subunit stoichiometry not defined
  2. 2011 High

    Showed LRRC26 reshapes BK pharmacology, distinguishing γ1-occupied from α-only channels through differential activator efficacy.

    Evidence Electrophysiology with mallotoxin and NS-1619 in native parotid acinar cells and heterologous parSlo ± LRRC26

    PMID:21984254

    Open questions at the time
    • Structural basis of mallotoxin sensitivity loss unresolved
    • Single lab
  3. 2014 High

    Demonstrated LRRC26 functions as a bona fide γ subunit in vascular smooth muscle, controlling myogenic tone.

    Evidence Co-IP, FRET, biotinylation, RNAi knockdown, and patch-clamp with myogenic tone measurement in cerebral artery myocytes

    PMID:24906643

    Open questions at the time
    • In vivo vascular consequences of loss not tested with a genetic model here
  4. 2018 Medium

    Identified a channel-independent role: LRRC26 suppresses NF-κB signaling and tumor-cell invasion, and is epigenetically silenced in cancer.

    Evidence siRNA/overexpression, NF-κB luciferase reporter, invasion/migration assays, bisulfite pyrosequencing and 5-aza-dC in triple-negative breast cancer cells

    PMID:29512727

    Open questions at the time
    • Molecular mechanism linking LRRC26 to NF-κB is not defined
    • Whether this is BK-dependent is untested
    • Single lab
  5. 2017 High

    Showed via genetic knockout that LRRC26 is required for BK-driven secretory function in epithelia, linking the gating shift to organismal K⁺ secretion.

    Evidence LRRC26 KO mice with β-gal reporter, co-IP across lacrimal/parotid/colon, acinar patch-clamp, and saliva ion analysis

    PMID:28416688

    Open questions at the time
    • Quantitative contribution to fluid secretion across tissues not fully partitioned
  6. 2019 Medium

    Extended γ1 occupancy to bronchial smooth muscle, distinguishing it functionally from aortic SMC by gating and mallotoxin response.

    Evidence Co-IP, TIRF imaging, whole-cell patch-clamp, qPCR and Western in bronchial vs. aortic SMCs

    PMID:31800260

    Open questions at the time
    • Physiological/airway consequences not tested in vivo
    • Single lab
  7. 2021 High

    Connected LRRC26-associated BK activity in colonic goblet cells to transepithelial K⁺ current and protection from colitis.

    Evidence LRRC26 KO and MUC2-reporter mice, goblet-cell patch-clamp, transepithelial current measurements, DSS colitis model

    PMID:33431687

    Open questions at the time
    • Mechanistic link between goblet-cell K⁺ flux and mucosal barrier protection not fully defined
  8. 2026 High

    Resolved the gating mechanism, showing γ1 acts on the closed-open transition and coupling rather than voltage-sensor movement.

    Evidence Macroscopic, single-channel, and gating-current measurements of BKα ± LRRC26 in heterologous expression

    PMID:41701845

    Open questions at the time
    • Atomic-level interface mediating coupling enhancement not defined
  9. 2026 High

    Defined the functional stoichiometry, showing one γ1 per BKα tetramer suffices for full modulation (all-or-none).

    Evidence Concatenated tandem BKα constructs with fused γ1, mutagenesis, and voltage-clamp in heterologous cells

    PMID:41784352

    Open questions at the time
    • Whether native channels carry one vs. multiple γ1 subunits not measured
    • Structural arrangement of the single γ1 not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular mechanism by which LRRC26 suppresses NF-κB signaling, and whether this is separable from its BK channel role, remains unresolved.
  • No direct LRRC26 binding partner in the NF-κB pathway identified
  • No structural model of the BKα–γ1 interface
  • Native subunit stoichiometry in tissue uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-382551 Transport of small molecules 2
Partners
KCNMA1
Complex memberships
BK (BKα/Slo1) channel complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 LRRC26 is an auxiliary protein of BK (BKα) channels that produces an unprecedented ~140 mV negative shift in voltage dependence, enabling BK channel activation at resting voltage without elevated cytosolic Ca²⁺. The mechanism involves enhanced allosteric coupling between voltage-sensor activation and the channel's closed-open transition. Electrophysiology (patch-clamp) in LNCaP prostate cancer cells and heterologous expression; functional characterization of BKα–LRRC26 complex Nature High 20613726
2011 LRRC26 selectively alters the pharmacology of BK channels: it strongly inhibits the ability of mallotoxin (MTX) to activate BK channels (reducing MTX-induced voltage shift from ~70 mV to ~6 mV) while having only a small effect on NS-1619 activation, indicating that the accessory protein differentially modulates activator efficacy. Electrophysiology in native parotid acinar cells and heterologous expression of parSlo ± LRRC26; pharmacological assays with MTX and NS-1619 Molecular pharmacology High 21984254
2014 In arterial smooth muscle cells, LRRC26 co-localizes with and co-immunoprecipitates with plasma membrane BKα subunits. LRRC26 knockdown reduces BK channel voltage sensitivity and apparent Ca²⁺ sensitivity, decreases transient BK current frequency and amplitude, and increases myogenic tone, establishing LRRC26 as a functional BK channel γ subunit in vascular smooth muscle. Co-immunoprecipitation, FRET microscopy, biotinylation (surface localization), RNAi knockdown, patch-clamp electrophysiology, myogenic tone measurements in cerebral artery myocytes Circulation research High 24906643
2017 LRRC26 (γ1) co-assembles with BK α-subunits specifically in secretory epithelial cells (lacrimal gland, parotid gland, colon). In LRRC26 KO mice, BK channel gating in acinar cells shifts to resemble α-subunit-only channels (rightward voltage shift), and salivary [K⁺] is reduced, demonstrating LRRC26 is required for BK channel activation at physiological resting potentials to support secretory function. LRRC26 KO mice with β-gal reporter, co-immunoprecipitation in multiple tissues, patch-clamp in acinar cells, ion composition analysis of saliva Proceedings of the National Academy of Sciences of the United States of America High 28416688
2019 In bronchial smooth muscle cells (BSMCs), LRRC26 (γ1) is highly expressed and interacts with BKα (shown by co-immunoprecipitation and TIRF imaging). BK channel steady-state activation in BSMCs occurs at more negative voltages (resembling BKα/γ1 reconstituted channels) compared to aortic SMCs or BKα-only channels. Mallotoxin (a BK activator selective for channels lacking γ1) activates BK currents in aortic SMCs but not in BSMCs, functionally confirming γ1 occupancy. Co-immunoprecipitation, total internal reflection fluorescence (TIRF) imaging, whole-cell patch-clamp electrophysiology, real-time PCR, Western blot in bronchial SMCs vs. aortic SMCs American journal of physiology. Lung cellular and molecular physiology Medium 31800260
2021 LRRC26-associated BK channels are present and functionally active specifically in colonic goblet cells (GCs) at physiological conditions; in LRRC26 KO mice, BK channels are present in GCs but not activated under physiological conditions. LRRC26-associated BK channels underlie the resting transepithelial K⁺ current across distal colonic mucosa, and genetic ablation of LRRC26 (or BK α-subunit) dramatically increases susceptibility to DSS-induced colitis. LRRC26 KO mice, MUC2-fluorescent reporter mice, patch-clamp in isolated GCs, transepithelial current measurements, DSS colitis model Proceedings of the National Academy of Sciences of the United States of America High 33431687
2018 LRRC26 negatively regulates NF-κB signaling in triple-negative breast cancer cells. LRRC26 overexpression reduces TNF-α-mediated NF-κB luciferase reporter activity and downstream gene expression (IL-6, IL-8, CXCL1), while LRRC26 knockdown upregulates these NF-κB target genes. LRRC26 knockdown also enhances anchorage-independent growth, invasion, and migration. Loss of LRRC26 expression is associated with promoter methylation (restored by 5-aza-dC treatment). siRNA knockdown and ectopic overexpression, NF-κB luciferase reporter assay, anchorage-independent growth assay, invasion/migration assays, bisulfite pyrosequencing, 5-aza-dC treatment International journal of oncology Medium 29512727
2026 Using macroscopic, single-channel, and gating-current measurements, LRRC26 (γ1) is shown to increase the equilibrium constant for BK channel closed-open transition by ~106-fold at zero mV by destabilizing the closed state and enhancing voltage-sensor–pore coupling, without affecting voltage-sensor activation per se. This clarifies a mechanistic controversy by identifying that γ1 primarily enhances the channel-opening reaction and energetic coupling, not voltage-sensor movement. Macroscopic patch-clamp, single-channel recordings, and gating-current measurements in heterologous expression of BKα ± LRRC26 (γ1) Proceedings of the National Academy of Sciences of the United States of America High 41701845
2026 Using concatenated BKα constructs (tandem dimers and tetramers), a single LRRC26 (γ1) subunit per BKα tetramer is sufficient to fully shift BK channel voltage activation (all-or-none stoichiometry), distinct from the stoichiometrically graded effect of a deep-pore L312A mutation and the all-four-subunit requirement for V288A selectivity filter inactivation. Concatenated tandem BKα subunit constructs with fused γ1, co-expression, electrophysiology (voltage-clamp) in heterologous expression system eLife High 41784352

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 LRRC26 auxiliary protein allows BK channel activation at resting voltage without calcium. Nature 196 20613726
2014 LRRC26 is a functional BK channel auxiliary γ subunit in arterial smooth muscle cells. Circulation research 62 24906643
2011 The LRRC26 protein selectively alters the efficacy of BK channel activators. Molecular pharmacology 37 21984254
2017 Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells. Proceedings of the National Academy of Sciences of the United States of America 30 28416688
2021 Goblet cell LRRC26 regulates BK channel activation and protects against colitis in mice. Proceedings of the National Academy of Sciences of the United States of America 22 33431687
2018 Frequent downregulation of LRRC26 by epigenetic alterations is involved in the malignant progression of triple-negative breast cancer. International journal of oncology 15 29512727
2019 Roles of LRRC26 as an auxiliary γ1-subunit of large-conductance Ca2+-activated K+ channels in bronchial smooth muscle cells. American journal of physiology. Lung cellular and molecular physiology 9 31800260
2025 Tuning the gate and the gear: The LRRC26 ( ) subunit modulates intrinsic gating and voltage-sensor coupling of the BK channel. bioRxiv : the preprint server for biology 1 40950215
2026 Tuning the gate and the gear: The LRRC26 (γ1) subunit modulates intrinsic gating and voltage-sensor coupling of the BK channel. Proceedings of the National Academy of Sciences of the United States of America 0 41701845
2026 Concatenated modular BK channel constructs reveal divergent stoichiometry in gating control by LRRC26 (γ1), pore, and selectivity filter. eLife 0 41784352
2016 Correction to"The LRRC26 Protein Selectively Alters the Efficacy of BK Channel Activators". Molecular pharmacology 0 31265510

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