Nitric oxide and carbon monoxide activate locus coeruleus neurons through a cGMP-dependent protein kinase: involvement of a nonselective cationic channel.
Nitric oxide (NO) and carbon monoxide (CO) have been identified as two diffusible signaling messengers in the brain, capable of stimulating soluble guanylate cyclase. Locus coeruleus (LC) is rich in the alpha 1 and beta 1 subunits of soluble guanylate cyclase. Therefore, the possible role of the cGMP pathway in the regulation of LC neurons was investigated with electrophysiological techniques in rat brain slices. Bath application of various NO donors or CO-containing solutions increased the firing rate of most LC neurons. This activation was reversed by the NO scavenger hemoglobin, but not by methemoglobin. Bath or intracellular application of selective activators of cGMP-dependent protein kinase also caused increases in LC cell firing rate. The actions of NO donors and kinase activators were mutually occlusive and reversed by H8, an inhibitor of the cGMP-dependent protein kinase. Hemoglobin and H8 reduced the firing rate of LC neurons, but no change was found with inhibitors or activators of the NO synthase. In intracellular and whole-cell recordings, NO effect was associated with an inward current and an increase in the input conductance (mean reversal potential = -27 mV); these effects were abolished using a low-sodium buffer. Spontaneous EPSCs of LC cells were not modified with the NO donor administration. Taken together, these data suggest that NO and CO activate noradrenergic neurons of LC via a cGMP-dependent protein kinase and a nonselective cationic channel. It also is proposed that these effects occur at the postsynaptic level and that there may be a tonic regulation of LC neuronal firing by the cGMP pathway.
Pineda
J
J
Department of Psychiatry, Yale University School of Medicine, New Haven 06508, USA.
Kogan
J H
JH
Aghajanian
G K
GK
D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D006152:Cyclic GMP / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects*; D008125:Locus Coeruleus / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009569:Nitric Oxide / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011494:Protein Kinases / Q000187:drug effects*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
D007473:Ion Channels; D009569:Nitric Oxide; D002248:Carbon Monoxide; D011494:Protein Kinases; D006152:Cyclic GMP