Persistent enhancement of neuronal excitability could sensitize neurons to excitotoxic death. Modulation of resting K⁺ currents has a profound influence on neuronal excitability. Among the KCNK family of two-pore-domain K⁺ channels, the pH-sensitive subunits TWIK-related acid-sensitive K⁺-1 (TASK-1) and TASK-3 are highly expressed in motoneurons. Injury of motor axons induces changes in motoneuron excitability and the de novo expression of the neuronal isoform of nitric oxide (NO) synthase (NOS-I), which has been involved in neuronal degeneration. Peripheral XIIth nerve injury in adult rats induced de novo NOS-I expression in hypoglossal motoneurons and an increased incidence of low-threshold motor units, the latter being mediated by the neuronal NO/cGMP pathway. In slice preparations, persistent, but not acute, activation of the NO/cGMP/protein kinase G (PKG) pathway evoked an augment in motoneuron excitability accompanied by inhibition of TASK-like currents. NO/PKG-action involved phosphorylation of the ATF-1 transcription factor, up-regulation of RhoA protein levels and required RhoA/Rho-kinase (ROCK) activity. NO-ROCK signalling did not alter total levels of TASK subunits, but increased TASK-1 localization in the endoplasmic reticulum-enriched fractions obtained by sucrose gradient fractionation. We find evidence for the involvement of this long-term mechanism in regulating membrane excitability of neonatal motoneurons, because their pH-sensitive currents were drastically reduced after nerve injury by a partially NO-dependent mechanism. Given that TASK channels are widely expressed throughout brain, this long-term mechanism regulating neuronal excitability could be a neuron-sensitizing pathway to glutamate-induced excitotoxicity in pathological conditions.

Supported by MCYT (SAF2005-00585) and CICE de la Junta de Andalucía (PAI05-CTS-00844 and PAI07-CTS-02606), Spain.