Nakamura, T. Y. | bioRxiv Science

bioRxiv2025

Structure-function analysis of lithium-ion selectivity of voltage-gated sodium channel

Voltage-gated sodium channels (Navs) selectively conduct Na+ to generate action potentials. Na+ permeates Navs with significantly higher efficiency than many other cations, but Li+ can also permeate Navs to a comparable extent as Na+. It had been known that Li+ in blood enters cell via Navs and effects beneficially on various neuropathies. However, the molecular basis of the high Li+ selectivity of Navs had been unclear. In this study, using a prokaryotic Nav, we successfully created the first Nav mutant that is more selective for Li+ than for Na+. Electrophysiological and crystallographic analyses revealed the critical determinants of high Li+ selectivity: the strong electrostatic interaction between the ion pathway and hydrated ions, and the smaller number of hydration water exchanges within the ion pathway. Additionally, the extensive interactions around the ion pathway were shown to support monovalent cation selectivity. New drug directions based on the molecular basis for Li+ permeation may target various neurological disorders and clarify the broader biological effects of lithium.

biophysics↗

bioRxiv2024

Kir6.1, a component of an ATP-sensitive potassium channel, regulates natural killer cell development

AO_SCPLOWBSTRACTC_SCPLOWInvolved in immunity and reproduction, natural killer (NK) cells offer opportunities to develop new immunotherapies to treat infections and cancer or to alleviate pregnancy complications. Most current strategies use cytokines or antibodies to enhance NK-cell function, but none use ion channel modulators, which are widely used in clinical practice to treat hypertension, diabetes, epilepsy, and other conditions. Little is known about ion channels in NK cells. We show that Kcnj8, which codes for the Kir6.1 subunit of a certain type of ATP-sensitive potassium (KATP) channel, is highly expressed in murine splenic and uterine NK cells compared to other K+ channels previously identified in NK cells. Kcnj8 expression is highest in the most mature subset of splenic NK cells (CD27-CD11b+) and in NKG2A+ or Ly49C/I+ educated uterine NK cells. Using patch clamping, we show that a subset of NK cells expresses a current sensitive to the Kir6.1 blocker PNU-37883A. Kcnj8 does not participate in NK cell degranulation in response to tumor cells in vitro or rejection of tumor cells in vivo. Transcriptomics show that genes previously implicated in NK cell development are amongst those differentially expressed in CD27-CD11b+ NK cells deficient of Kcnj8. Indeed, we found that mice with NK-cell specific Kcnj8 gene ablation have fewer CD11b+CD27- and KLRG-1+ NK cells in the bone barrow and spleen. These results show that the KATP subunit Kir6.1 has a key role in NK-cell development.

immunology↗