Slack K ⁺ channels attenuate NMDA‐induced excitotoxic brain damage and neuronal cell death

The neuronal Na+-activated K+ channel Slack (aka Slo2.2, KNa1.1, or Kcnt1) has been implicated in setting and maintaining the resting membrane potential defining excitability firing patterns, as well generation of slow afterhyperpolarization following bursts action potentials. activity increases significantly under conditions high intracellular Na+ levels, suggesting this may exert important pathophysiological functions. To address these putative roles, we studied whether channels contribute to pathological changes excitotoxic cell death caused by glutamatergic overstimulation Ca2+- Na+-permeable N-methyl-D-aspartic acid receptors (NMDAR). Slack-deficient (Slack KO) wild-type (WT) mice were subjected intrastriatal microinjections NMDAR agonist NMDA. NMDA-induced brain lesions increased KO vs WT mice, that lack renders neurons particularly susceptible excitotoxicity. Accordingly, excessive was seen primary cerebellar granule (CGC) cultures exposed glutamate Differences survival between CGCs largely abolished antagonist MK-801, but not NBQX, a potent highly selective competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic (AMPA)-type ionotropic receptors. Interestingly, NMDAR-evoked Ca2+ signals did differ with regard genotype CGCs. However, real-time monitoring activation revealed significant contribution drop K+. Finally, TrkB TrkC neurotrophin receptor transcript levels elevated NMDA-exposed Slack-proficient CGCs, mechanism which contributes extracellular-signal-regulated kinase (Erk) pathway thereby neuroprotection. Combined, our findings suggest Slack-dependent oppose NMDAR-mediated injury promoting pro-survival signaling via BDNF/TrkB Erk axis.