Key result
Kv9.1Val variant reduces Kv2.1 surface expression more than Kv9.1Ile, suggesting a pain hypersensitivity mechanism.
Why the study?
A common Kv9.1 Ile489Val allele is associated with pain hypersensitivity, but the underlying regulatory mechanism on Kv2.1 properties remains unknown.
The Ile489Val substitution in Kv9.1 produces a greater reduction in Kv2.1 surface expression, which may underlie its association with pain hypersensitivity.
May link Kv9.1 variants to pain models; leaves open human translation and therapeutic targeting.
Background/Objectives: Kv2 channels have important conducting and nonconducting functions and are regulated by their co-assembly with ‘silent’ Kv subunits, including Kv9.1. Kv9.1 is co-expressed with Kv2 channels in sensory neurons, and a common allele that changes Ile489 to Val in human Kv9.1 is associated with pain hypersensitivity in patients. The mechanism responsible for this association remains unknown, but we hypothesise that these two variants differ in their regulation of Kv2.1 properties, and this is what we set out to test. Methods: Expression was carried out using HEK293 cells, OHeLa cells, and primary cultures of hippocampal neurons, and the biophysical and trafficking properties of homomeric and heteromeric channels were assessed by confocal fluorescence microscopy and patch clamp analysis. Results: Both Kv9.1Ile and Kv9.1Val were retained within the endoplasmic reticulum when expressed individually, but when co-expressed with Kv2.1, they co-localised with Kv2.1 within the surface clusters. Both variants reduced the surface expression of Kv2.1 channels and the size of channel clusters, with Kv9.1Val producing a greater reduction in surface expression in both the HeLa cells and neurons. They both caused a similar hyperpolarising shift in the voltage dependence of channel activation and inactivation. Concatamers of Kv2.1 and Kv9.1 suggested that both 3:1 and 2:2 ratios of Kv2.1 to Kv9.1 were permitted, although 2:2 resulted in lower surface expression and function. Conclusions: The Ile489Val substitution in Kv9.1 does not disrupt its ability to co-assemble with Kv2 channels, nor its effects on the voltage-dependence of channel gating, but it did produce a greater reduction in the Kv2.1 surface expression, suggesting that this underlies its association with pain hypersensitivity.
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Choudhury et al. (2025) studied this question. Kv9.1Val variant vs. Kv9.1Ile variant was evaluated on Surface expression of Kv2.1 channels. The Kv9.1Val variant produced a greater reduction in Kv2.1 surface expression than the Kv9.1Ile variant in both HeLa cells and neurons, suggesting a mechanism for pain hypersensitivity.
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