Coupling of muscarinic cholinergic receptors and cGMP in nocturnal regulation of the suprachiasmatic circadian clock
| Autor: | Martha U. Gillette, Lia E. Faiman, Chen Liu, Jian M. Ding |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Atropine
medicine.medical_specialty Carbachol Indoles Time Factors Circadian clock Carbazoles Cholinergic Agents Nerve Tissue Proteins Gating Muscarinic Antagonists Biology Alkaloids Internal medicine medicine Cyclic GMP-Dependent Protein Kinases Animals Circadian rhythm Enzyme Inhibitors Cyclic GMP Basal forebrain Afferent Pathways Suprachiasmatic nucleus General Neuroscience Rats Inbred Strains Articles Receptors Muscarinic Acetylcholine Circadian Rhythm Rats Endocrinology Cholinergic Fibers Guanylate Cyclase Aminoquinolines Cholinergic Suprachiasmatic Nucleus medicine.drug Signal Transduction |
| Zdroj: | The Journal of neuroscience : the official journal of the Society for Neuroscience. 17(2) |
| ISSN: | 0270-6474 |
| Popis: | Acetylcholine has long been implicated in nocturnal phase adjustment of circadian rhythms, yet the subject remains controversial. Although the suprachiasmatic nucleus (SCN), site of the circadian clock, contains no intrinsic cholinergic somata, it receives choline acetyltransferase-immunopositive projections from basal forebrain and mesopontine tegmental nuclei that contribute to sleep and wakefulness. We have demonstrated that the SCN of inbred rats in a hypothalamic brain slice is sensitive to cholinergic phase adjustment via muscarinic receptors (mAChRs) only at night. We used this paradigm to probe the muscarinic signal transduction mechanism and the site(s) gating nocturnal responsiveness. The cholinergic agonist carbachol altered the circadian rhythm of SCN neuronal activity in a pattern closely resembling that for analogs of cGMP; nocturnal gating of clock sensitivity to each is preservedin vitro.Specific inhibitors of guanylyl cyclase (GC) and cGMP-dependent protein kinase (PKG), key elements in the cGMP signal transduction cascade, blocked phase shifts induced by carbachol. Further, carbachol administration to the SCN at night increased cGMP production and PKG activity. The carbachol-induced increase in cGMP was blocked both by atropine, an mAChR antagonist, and by LY83583, a GC inhibitor. We conclude that (1) mAChR regulation of the SCN is mediated via GC→cGMP→PKG, (2) nocturnal gating of this pathway is controlled by the circadian clock, and (3) a gating site is positioned downstream from cGMP. This study is among the first to identify a functional context for mAChR–cGMP coupling in the CNS. |
| Databáze: | OpenAIRE |
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