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 t...

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Published in:Journal of neurophysiology 2012-03, Vol.107 (5), p.1489-1499
Main Authors: Wenker, Ian C, Benoit, Justin P, Chen, Xinnian, Liu, Hattie, Horner, Richard L, Mulkey, Daniel K
Format: Article
Language:English
Subjects:
Animals
Cyclic GMP - physiology
Cyclic Nucleotide-Gated Cation Channels - metabolism
Hypoglossal Nerve - physiology
Male
Motor Neurons - physiology
Nitric Oxide - physiology
Potassium Channels, Tandem Pore Domain - antagonists & inhibitors
Potassium Channels, Tandem Pore Domain - physiology
Rats
Rats, Wistar
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Summary: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 Ba(2+)-sensitive background K(+) conductance and activated a Cs(+)-sensitive hyperpolarization-activated inward current (I(h)). When I(h) 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 I(h) in relative isolation, we tested effects of NO in the presence of Ba(2+) to block TASK channels. Under these conditions, NO activated both the instantaneous (I(inst)) and time-dependent (I(ss)) components of I(h). Interestingly, at more hyperpolarized potentials NO preferentially increased I(inst). The effects of NO on I(h) 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 I(h).
ISSN:0022-3077
1522-1598
DOI:10.1152/jn.00827.2011