Serotonin receptor 1A-modulated dephosphorylation of glycine receptor α3: A new molecular mechanism of breathing control for compensation of opioid-induced respiratory depression without loss of analgesia. [Die von Serotoninrezeptor 1A modulierte Dephosphorylierung des Glyzinrezeptors α3]

Manzke, T., Niebert, M., Koch, U.R., Caley, A., Vogelgesang, S., Bischoff, A-M., Hülsmann, S., Ponimaskin, E., Müller, U., Smart, T.G., Harvey, R.J. and Richter, D.W. (2011) Serotonin receptor 1A-modulated dephosphorylation of glycine receptor α3: A new molecular mechanism of breathing control for compensation of opioid-induced respiratory depression without loss of analgesia. [Die von Serotoninrezeptor 1A modulierte Dephosphorylierung des Glyzinrezeptors α3]. Schmerz, 25 (3). pp. 272-281. 10.1007/s00482-011-1044-1.

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DOI: 10.1007/s00482-011-1044-1

Abstract

To control the breathing rhythm the medullary respiratory network generates periodic salvo activities for inspiration, post-inspiration and expiration. These are under permanent modulatory control by serotonergic neurons of the raphe which governs the degree of phosphorylation of the inhibitory glycine receptor α3. The specific activation of serotonin receptor type 1A (5-HTR 1A), which is strongly expressed in the respiratory neurons, functions via inhibition of adenylate cyclase and the resulting reduction of the intracellular cAMP level and a gradual dephosphorylation of the glycine receptor type α3 (GlyRα3). This 5-HTR 1A-GlyRα3 signal pathway is independent of the μ-opioidergic transduction pathway and via a synaptic inhibition caused by an increase in GlyRα3 stimulates a disinhibition of some target neurons not only from excitatory but also from inhibitory neurons. Our physiological investigations show that this 5-HTR 1A-GlyRα3 modulation allows treatment of respiratory depression due to opioids without affecting the desired analgesic effects of opioids. The molecular mechanism presented here opens new pharmacological possibilities to treat opioid-induced respiratory depression and respiratory disorders due to disturbed inhibitory synaptic transmission, such as hyperekplexia.

Item Type:Article
Uncontrolled Keywords:Adenylate cyclase; Opioids; Phosphorylation; Respiratory depression; Serotinin 1A receptor
Departments, units and centres:Department of Pharmacology > Department of Pharmacology
ID Code:2779
Journal or Publication Title:Schmerz
Deposited By:Library Staff
Deposited On:10 Feb 2012 09:56
Last Modified:10 Feb 2012 09:57

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