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M-current channel assembly

Zhaowen Luo , Ji Sun

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Vita > Cutting Edge > DOI: 10.15302/vita.2026.05.0036
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M-current channel assembly

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The M-current is a potassium current conducted by heteromeric KCNQ2–KCNQ3 channels. Two recent studies1,2 published in Vita elucidate the structural bases of channel assembly and activation, revealing different stoichiometric arrangements and sites for pharmacological intervention.

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The neuronal M-current is a slowly activating, non-inactivating voltage-gated potassium current that serves as a major brake on neuronal excitability. First described by Brown and Adams in sympathetic neurons3, the M-current activates near resting membrane potential, stabilizes membrane voltage, and promotes spike-frequency adaptation. Its suppression by muscarinic acetylcholine receptor signaling converts adapting firing into sustained tonic activity, thereby enhancing neuronal responsiveness4 (Fig. 1a). The M-current was shown to be mediated by heteromeric KCNQ2–KCNQ3 channels5, which are gated by voltage and phosphatidylinositol 4,5 biphosphate (PIP2), thus accounting for the suppressing effect of muscarinic acetylcholine receptor (Fig. 1b). Reflecting their direct role in mediating M-current, dysfunction of KCNQ2–KCNQ3 channels is tightly linked to epilepsy and related hyperexcitability disorders.
Despite decades of investigation, the stoichiometry and subunit arrangement of native M-channels have remained unresolved. Early functional and pharmacological studies supported a predominant 1:1 KCNQ2:KCNQ3 ratio6, but more recent work has proposed a flexible assembly model in which asymmetric heterotetramers form, depending on relative subunit expression levels, with important consequences for gating behavior, current density, and subcellular targeting7. Resolving this long-standing question has proven challenging using functional approaches alone.
In this issue, two independent studies by Lu et al.2 and Wang et al.1 provide the first high-resolution structural views of heteromeric KCNQ2–KCNQ3 channel assemblies (Fig. 1c, d). Using recombinant co-expression and two-step affinity purification strategies, both groups resolved the architecture of the heterotetramer and arrived at different conclusions regarding stoichiometry. Wang et al.1 observed a continuum of assemblies, spanning 1:3, 2:2, and 3:1 KCNQ2:KCNQ3 ratios (Fig. 1d), and used concatenated constructs to demonstrate the functional relevance of such heterogeneity at both macroscopic and single-channel levels. By contrast, Lu et al.2 identified a dominant 3:1 KCNQ2:KCNQ3 configuration, alongside a minor 2:2 population (Fig. 1c). Both studies suggested that subunit stoichiometry may be influenced by their relative expression levels. Adding to this complication, a recent study by Cheng et al. reports a predominant 1:3 KCNQ2:KCNQ3 stoichiometry, while detecting the full range of possible subunit ratios8.
Beyond stoichiometry of the channel complex, both studies illuminate the structural basis of the M-current’s subthreshold activation. Although KCNQ3 forms non-conductive homotetramers, it plays a key role in facilitating voltage-sensor activation within heteromeric channels. In both structures, the S4 helix of KCNQ3 adopts a more activated conformation than that of KCNQ2, potentially lowering the energetic barrier for voltage-sensor movement and enabling channel opening at relatively lower membrane potentials.
These insights arrive at a critical moment for M-current-directed therapeutics. Enhancing KCNQ2–KCNQ3 activity is a validated strategy for suppressing neuronal hyperexcitability, as exemplified by the clinical efficacy of the KCNQ opener retigabine (also known as ezogabine), whose use was limited by tolerability and off-target effects. Both studies advance next-generation drug discovery by revealing distinct and pharmacologically tractable mechanisms of channel modulation. Lu et al.2 defined how compound ICA110381 stabilizes activated KCNQ2 voltage sensors9 and showed that XEN110110, a compound in phase III clinical trial, binds pore fenestrations to promote PIP2-assisted cooperative gating. Building on the structural insights from the KCNQ2 and retigabine complex, Wang et al.1 developed CLM142, a novel activator with markedly improved potency and specificity, and performed cryo-EM analysis to further define the compound’s binding mode; they also used CLM142 to analyze PIP2-dependent pore dilation of the channel complex.
Together, these complementary studies provide a structural framework for understanding KCNQ2–KCNQ3 channel assembly, gating, and pharmacological modulation. The native stoichiometry of M channels remains an open question, requiring structural characterization of channels from native tissues, diverse neuronal contexts and even different developmental stages. Nevertheless, the current work establishes a robust framework for structure-guided drug discovery efforts targeting this essential neuronal excitability regulator. By exposing multiple, mechanistically distinct binding sites within the heterotetrameric complex, these advances by Wang et al.1 and Lu et al.2 offer renewed optimism for the development of safer, more effective therapies for M-current-associated neurological diseases.

[1]

Wang, Y. et al. Vita https://doi.org/10.15302/vita.2026.05.0032 (2026).

[2]

Lu, F. et al. Vita https://doi.org/10.15302/vita.2026.05.0035 (2026).

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Brown, D.A. & Adams, P.R. Nature 283, 673–676 (1980).

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Delmas, P. & Brown, D.A. Nat. Rev. Neurosci. 6, 850–862 (2005).

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Wang, H.S. et al. Science 282, 1890–1893 (1998).

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Hadley, J.K. et al. J. Neurosci. 23, 5012–5019 (2003).

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Springer, K., Varghese, N. & Tzingounis, A.V. Dev. Neurosci. 43, 191–200 (2021).

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Cheng, X. et al. Cell Res. https://doi.org/10.1038/s41422-026-01261-5 (2026).

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Amato, G. et al. ACS Med. Chem. Lett. 2, 481–484 (2011).

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The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

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Luo, Z., Sun, J.  M-current channel assembly  Vita https://doi.org/10.15302/vita.2026.05.0036 ()
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