Sodium-Activated Potassium Channels Are Functionally Coupled to Persistent Sodium Currents

Abstract

We report a novel coupled system of sodium-activated potassium currents (IKNa) and persistent sodium currents (INaP), the components of which are widely distributed throughout the brain. Its existence and importance has not been previously recognized. Although IKNa was known to exist in many cell types, the source of Na+ which activates IKNa remained a mystery. We now show in single membrane patches generated from the somas of rat neurons that sodium influx through INaP is sufficient for activation of KNa channels, without substantial contribution from the transient sodium current or bulk [Na+]i. INaP was found to be active at cell membrane resting potentials, a finding that may explain why IKNa can be evoked from negative holding potentials. These results show an unanticipated role for INaP in activating a negative feedback system countering the excitable effects INaP; the interrelatedness of INaP and IKNa suggests new ways neurons can tune their excitability.

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

“…Thus we conclude that both TTXand Cd 2ϩ -sensitive I NaP may participate largely in elevating intracellular Na ϩ concentration ([Na ϩ ] i ) and accordingly activate K Na channels. These results are consistent with previous studies demonstrating that TTX-sensitive I NaP are the source of Na ϩ for the activation of K Na channels in tufted/mitral cells of the olfactory bulbs (Budelli et al 2009;Hage and Salkoff 2012).…”

“…Subsequently, considerable evidence has accumulated showing that K Na channels play a role in the regulation of neuronal excitability (Schwindt et al 1989), the modulation of action potential waveform (Dryer 1994), and the response of excitable cells to hypoxia and ischemia (Yuan et al 2003). Recently, it was shown that K Na channels are activated by Na ϩ influx through TTX-sensitive persistent Na ϩ channels in tufted/mitral cells of the olfactory bulb (Hage and Salkoff 2012), thus showing functional coupling between Na ϩ -activated K ϩ channels and TTX-sensitive persistent Na ϩ currents. K Na channels are found in insect neurons such as cockroach DUM neurons (Grolleau and Lapied 1994) and in cultured Drosophila neurons (Saito and Wu 1991).…”

An ALS-Associated Mutant SOD1 Rapidly Suppresses KCNT1 (Slack) Na+-Activated K+Channels inAplysiaNeurons

“…TTX, however, also completely eliminates K Na currents that are functionally coupled to the I NaP channels (Hage and Salkoff, 2012). The observed increase in I NaP in the animal models of ALS may therefore represent loss of K Na current rather than, or in addition to, increased Na ϩ current.…”

“…Some studies have pointed to an increase in a persistent voltage-dependent Na ϩ current as a cause of increased excitability, although changes in outward currents have also been reported (Kuo et al, 2005;Wainger et al, 2014). In neurons, however, the persistent Na ϩ current rapidly and selectively activates Na ϩ -activated K ϩ channels (K Na channels) (Hage and Salkoff, 2012). These are encoded by the Slack (K Na 1.1, Slo2.2, KCNT1) and Slick (K Na 1.2, Slo2.1, KCNT2) genes .…”

“…These are encoded by the Slack (K Na 1.1, Slo2.2, KCNT1) and Slick (K Na 1.2, Slo2.1, KCNT2) genes . The activation of these channels produces an outward current that directly opposes the inward current that flows through Na ϩ channels, and the resultant persistent current is determined by the balance of Na ϩ and K Na currents (Hage and Salkoff, 2012). Human genetic mutations in KCNT1 cause earlyonset epilepsies but also severely impact neuronal development and intellectual function, likely because these channels interact directly with proteins that regulate activity-dependent translation of mRNAs (Brown et al, 2010;Barcia et al, 2012;Heron et al, 2012;Kim and Kaczmarek, 2014).…”