Nitric oxide activates hypoglossal motoneurons by cGMP-dependent inhibition of TASK channels and cGMP-independent activation of HCN channels.

Nitric oxide (NO) is an important signaling molecule that regulates numerous physiological processes, including activity of respiratory motoneurons. However, molecular mechanism(s) underlying NO modulation of motoneurons remain obscure. Here, we used a combination of in vivo and in vitro recording techniques to examine NO modulation of motoneurons in the hypoglossal motor nucleus (HMN). Microperfusion of diethylamine (DEA; an NO donor) into the HMN of anesthetized adult rats increased genioglossus muscle activity. In the brain slice, whole cell current-clamp recordings from hypoglossal motoneurons showed that exposure to DEA depolarized membrane potential and increased responsiveness to depolarizing current injections. Under voltage-clamp conditions, we found that NO inhibited a Ba2+-sensitive background K+ conductance and activated a Cs+- sensitive hyperpolarization-activated inward current (Ih). When Ih was blocked with Cs+ or ZD-7288, the NO-sensitive K+ conductance exhibited properties similar to TWIK-related acid-sensitive K+ (TASK) channels, i.e., voltage independent, resistant to tetraethylammonium and 4-aminopyridine but inhibited by methanandamide. The soluble guanylyl cyclase blocker 1H-(1,2,4)oxadiazole(4,3-a)quinoxaline- 1-one (ODQ) and the PKG blocker KT-5823 both decreased NO modulation of this TASK-like conductance. To characterize modulation of Ih in relative isolation, we tested effects of NO in the presence of Ba2+ to block TASK channels. Under these conditions, NO activated both the instantaneous (Iinst) and time-dependent (Iss) components of Ih. Interestingly, at more hyperpolarized potentials NO preferentially increased Iinst. The effects of NO on Ih were retained in the presence of ODQ and blocked by the cysteine-specific oxidant N-ethylmaleimide. These results suggest that NO activates hypoglossal motoneurons by cGMP-dependent inhibition of a TASK-like current and S-nitrosylation-dependent activation of Ih. [ABSTRACT FROM AUTHOR]