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Carbon monoxide and nitric oxide: interacting messengers in muscarinic signaling to the brain's circadian clock.
- Source :
-
Experimental neurology [Exp Neurol] 2001 Oct; Vol. 171 (2), pp. 293-300. - Publication Year :
- 2001
-
Abstract
- Within the central nervous system, acetylcholine (ACh) functions as a state-dependent modulator at a range of sites, but its signaling mechanisms are yet unclear. Cholinergic projections from the brain stem and basal forebrain innervate the suprachiasmatic nucleus (SCN), the master circadian clock in mammals, and cholinergic stimuli adjust clock timing. Cholinergic effects on clock state require muscarinic receptor-mediated activation of guanylyl cyclase and cGMP synthesis, although the effect is indirect. Here we evaluate the roles of carbon monoxide (CO) and nitric oxide (NO), major activators of cGMP synthesis. Both heme oxygenase 2 (HO-2) and neuronal nitric oxide synthase (nNOS), enzymes that synthesize CO and NO, respectively, are expressed in rat SCN, with HO-2 localized to the central core of the SCN, whereas nNOS is a punctate plexus. Hemin, an activator of HO-2, but not the NO donor, SNAP, mimicked cholinergic effects on circadian timing. Selective inhibitors of HO fully blocked cholinergic clock resetting, whereas NOS inhibition partially attenuated this effect. Hemoglobin, an extracellular scavenger of both NO and CO, blocked cholinergic stimulation of cGMP synthesis, whereas l-NAME, a specific inhibitor of NOS, had no effect on cholinergic stimulation of cGMP, but decreased the cGMP basal level. We conclude that basal NO production generates cGMP tone that primes the clock for cholinergic signaling, whereas HO/CO transmit muscarinic receptor activation to the cGMP-signaling pathway that modulates clock state. In light of the recently reported inhibitory interaction between HO-2/CO and amyloid-beta, a marker of Alzheimer's disease (AD), we speculate that HO-2/CO signaling may be a defective component of cholinergic neurotransmission in the pathophysiology of AD, whose manifestations include disintegration of circadian timing.<br /> (Copyright 2001 Academic Press.)
- Subjects :
- Animals
Circadian Rhythm drug effects
Cyclic GMP metabolism
Heme Oxygenase (Decyclizing) metabolism
Immunohistochemistry
In Vitro Techniques
NG-Nitroarginine Methyl Ester pharmacology
Nitric Oxide Donors pharmacology
Nitric Oxide Synthase metabolism
Nitric Oxide Synthase Type I
Rats
Rats, Long-Evans
Receptors, Cholinergic physiology
Receptors, Muscarinic drug effects
S-Nitroso-N-Acetylpenicillamine pharmacology
Signal Transduction
Suprachiasmatic Nucleus physiology
Synaptic Transmission physiology
Brain physiology
Carbon Monoxide physiology
Circadian Rhythm physiology
Nitric Oxide physiology
Receptors, Muscarinic physiology
Subjects
Details
- Language :
- English
- ISSN :
- 0014-4886
- Volume :
- 171
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Experimental neurology
- Publication Type :
- Academic Journal
- Accession number :
- 11573981
- Full Text :
- https://doi.org/10.1006/exnr.2001.7781