Pharmacological activation and inhibition of Slack (Slo2.2) channels

Slack and Slick KNaChannels Regulate the Accuracy of Timing of Auditory Neurons

“…The increases in macroscopic currents with 20 or 60 mM internal Na ϩ were statistically significant ( p Ͻ 0.0004 for 20 mM Na ϩ and p Ͻ 0.0002 for 60 mM Na ϩ at ϩ80 to ϩ120 mV). Previous studies have identified quinidine as a potent inhibitor of both Slack and Slick currents (Bhattacharjee et al, 2003;Yang et al, 2006). Bath application of 1 mM quinidine greatly inhibited the Na ϩ -sensitive component of whole-cell K ϩ current in MNTB neurons (Fig.…”

“…Nevertheless, because the anti-mouse secondary antibody did not recognize any morphological structure resembling either the neurons or synaptic terminals in the MNTB, we considered the staining of the calyceal terminals to be specific. K Na channels from MNTB neurons resemble Slack and Slick channels in expression systems When expressed in Xenopus oocytes, Chinese hamster ovary (CHO) , and human embryonic kidney (HEK) cells, Slack and Slick give rise to outwardly rectifying potassium channels that have unitary conductances of ϳ140 and ϳ180 pS, respectively, in symmetrical potassium solutions (Joiner et al, 1998;Bhattacharjee et al, 2003;Yang et al, 2006). Channels encoded by both genes are gated by increases in intracellular Na ϩ concentrations.…”

“…In this study, we have localized and identified K Na channels in the principal neurons of the MNTB and have compared their properties with those of Slack and Slick expressed in oocytes and mammalian cell lines (Joiner et al, 1998;Bhattacharjee et al, 2003;Yuan et al, 2003;Santi et al, 2006;Yang et al, 2006). Current-clamp recordings from MNTB neurons and numerical simulations indicate that the activation of these K Na channels allows temporal accuracy of firing to be increased at high frequencies of stimulation.…”

Na + -mediated coupling between AMPA receptors and K Na channels shapes synaptic transmission

“…To confirm that the Li ϩ effect on the decay of the AMPA-induced EPSC is caused by a blockade of K Na channels, we tested the effect of the K Na activator bithionol, which is known to activate Slack channels (23). We first tested the effect of bithionol on the amplitude of the activated K Na current in the dissociated lamprey spinal neurons.…”

KCNT1 gain-of-function mutations linked to human epilepsy are modulated by quinidine

“…KCNT1 linked early-onset epileptic syndromes are refractory with devastating clinical severity [7][8][9][10] , generating a serious need for effective therapies. This prompted us to investigate the effects of quinidine; an FDA approved antiarrhythmic compound and an earlier proven blocker of rodent KCNT1 channels [12][13] . We found that quinidine resulted in inhibition of the current amplitude of human WT and all pathogenic mutations and in some cases reversed the gain-of-function towards a WT phenotype.…”