Opposite Regulation of Slick and Slack K⁺Channels by Neuromodulators

Abstract

. We now report that activity of both Slo2 channels is controlled by neuromodulators through G␣ q -protein coupled receptors (GqPCRs) (the M 1 muscarinic receptor and the mGluR1 metabotropic glutamate receptor). Experiments coexpressing channels and receptors in Xenopus oocytes show that Slo2.1 and Slo2.2 channels are modulated in opposite ways: Slo2.1 is strongly inhibited, whereas Slo2.2 currents are strongly activated through GqPCR stimulation. Differential regulation involves protein kinase C (PKC); application of the PKC activator PMA, to cells expressing channels but not receptors, inhibits Slo2.1 whole-cell currents and increases Slo2.2 currents. Synthesis of a chimera showed that the distal carboxyl region of Slo2.1 controls the sensitivity of Slo2.1 to PMA. Slo2 channels have widespread expression in brain (Bhattacharjee et al., 2002, 2005). Using immunocytochemical techniques, we show coexpression of Slo2 channels with the GqPCRs in cortical and hippocampal brain sections and in cultured hippocampal neurons. The differential control of these novel channels by neurotransmitters may elicit long-lasting increases or decreases in neuronal excitability and, because of their widespread distribution, may provide a mechanism to activate or repress electrical activity in many systems of the brain.

Functional coupling between sodium-activated potassium channels and voltage-dependent persistent sodium currents in cricket Kenyon cells

“…Bithionol, a bis-phenol compound known for its antiparastic actions, potently activates Slack currents (Yang et al 2007). Activation of PKC increases the amplitude of Slack-B currents and decreases the amplitude of Slick currents (Santi et al 2006). Furthermore, a recent study shows that the Slick and Slack subunits coassemble to form heteromeric channels that differ from the homomers in their unitary conductance (Chen et al 2009).…”

PKA-Induced Internalization of Slack KNaChannels Produces Dorsal Root Ganglion Neuron Hyperexcitability

“…Both channel subunits contain large C termini consisting of tandem RCK domains (regulators of K ϩ conductance) (Jiang et al, 2002;Ye et al, 2006) with many consensus PKA and protein kinase C (PKC) phosphorylation sites (Joiner et al, 1998;Bhattacharjee et al, 2003). Although sensitive to PKC regulation (Santi et al, 2006), recombinant Slack channels are unresponsive to PKA modulation (Nuwer et al, 2009). Most of the PKA consensus in Slack are located outside the RCK domains, suggesting that PKA modulation of Slack K Na channels should not affect gating but could involve protein-protein interaction and consequently trafficking of channels.…”

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

“…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.…”