GRIN2B disease-associated mutations disrupt the function of BK channels and NMDA receptor signaling nanodomains

TL;DR

This paper shows that mutations in the GRIN2B gene disrupt interactions between NMDA receptors and BK channels, potentially explaining how these mutations lead to neurodevelopmental disorders.

Contribution

The study reveals that GRIN2B mutations impair nanoscale coupling between NMDA receptors and BK channels, offering a novel mechanistic insight into disease pathophysiology.

Findings

GRIN2B mutations V15M and V618G disrupt nanoscale coupling between NMDA receptors and BK channels.

Mutation V618G specifically impairs NMDA receptor-BK channel complex formation despite normal channel expression.

Abstract

Mutations in the GRIN2B gene, encoding the GluN2B subunit of NMDA receptors, are linked to neurodevelopmental disorders. We show that two variants disrupt nanoscale coupling between NMDA receptors and BK channels, revealing nanodomain dysfunction as a potential mechanism contributing to GRIN2B-associated pathophysiology.

Large conductance calcium-activated potassium channels (BK channels) are unique in their ability to respond to two distinct physiological stimuli: intracellular Ca2+ and membrane depolarization. In neurons, these channels are activated through a coordinated response to both signals; however, for BK channels to respond to physiological voltage changes, elevated concentrations of intracellular Ca2+ (ranging from 1 to 10 μM) are necessary. In many physiological contexts, BK channels are typically localized within nanodomains near Ca2+ sources (∼20–50 nm), such as N-methyl-D-aspartate receptors (NMDARs; encoded by the GRIN genes). Since the direct evidence of NMDAR–BK channel coupling reported by Isaacson and Murphy in 2001 in the olfactory bulb, further studies have identified functional coupling between NMDARs and BK channels in other regions of the brain, emphasizing their importance in neuronal function. Mutations in the genes encoding NMDAR subunits have been directly linked to developmental encephalopathies, including intellectual disability, epilepsy, and autism spectrum features. Specifically, mutations V15M and V618G in the GRIN2B gene, which encodes the GluN2B subunit of NMDARs, are implicated in the pathogenesis of GRIN2B-related neurodevelopmental disorders. Here, we explored the effects of these two GluN2B mutations on NMDAR–BK channel coupling, employing a combination of electrophysiological, biochemical, and imaging techniques. Taken together, our results demonstrate that mutation V618G specifically disrupts NMDAR–BK complex formation, impairing functional coupling, in spite of robust individual channel expression in the membrane. These results provide a potential mechanistic basis for GRIN2B-related pathophysiology and uncover new clues about NMDAR–BK complex formation.

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