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Die von Serotoninrezeptor 1A modulierte Dephosphorylierung des Glyzinrezeptors α3

Ein neuer molekularer Mechanismus der Atmungskontrolle zur Kompensation opioidinduzierter Atemdepression ohne Verlust der Analgesie

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

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Zusammenfassung

Zur Steuerung von Atembewegungen generiert das medulläre respiratorische Netzwerk periodische Salvenaktivitäten für die Inspiration, Postinspiration und Exspiration. Diese stehen unter ständiger modulatorischer Kontrolle durch serotonerge Neurone der Raphé, wodurch u. a. der Phosphorylierungsgrad des inhibitorischen Glyzinrezeptors α3 geregelt wird. Die spezifische Aktivierung des in den respiratorischen Neuronen stark exprimierten Serotoninrezeptors vom Typ 1A (5-HTR1A) bewirkt über die Hemmung der Adenylatzyklase und das resultierende Absenken des intrazellulären cAMP-Spiegels eine allmähliche Dephosphorylierung des Glyzinrezeptors vom Typ α3 (GlyRα3). Dieser 5-HTR1A-GlyRα3-Signalweg verläuft unabhängig vom μ-opioidergen Transduktionsweg und löst über eine verstärkte GlyRα3 ausgelöste synaptische Hemmung nicht nur von erregenden, sondern auch von hemmenden Neuronen, also auch eine Disinhibition mancher Zielneurone aus. Unsere physiologischen Untersuchungen zeigten, dass diese 5-HTR1A-GlyRα3-Modulation eine Behandlung der durch Opioide ausgelösten Atemdepression ermöglicht, ohne die erwünschte analgetische Wirkung der Opioide aufzuheben. Die hier dargestellten molekularen Mechanismen eröffnen neue pharmakologische Interventionsmöglichkeiten, um sowohl opioidinduzierte Atemdepression als auch Atmungsstörungen, welche ätiologisch auf einer gestörten inhibitorischen synaptischen Transmission beruhen, wie z. B. die Hyperekplexie, zu therapieren.

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-HTR1A), 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-HTR1A-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-HTR1A-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.

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Abbreviations

AC:

Adenylatzyklase

ACSF:

„artificial cerebrospinal fluid”

5-HT:

5-Hydroxytryptamin (Serotonin)

5-HTR:

Serotoninrezeptor

5-HTR1A :

Serotonin-1A-Rezeptor

BötC:

Bötzinger-Komplex

BSA:

Bovines Serum-Albumin

cAMP:

Zyklisches 3‘, 5‘-Adenosinmonophosphat

EDTA:

Ethylendiamintetraazetat

eGFP:

„enhanced green fluorescent protein“

GlyR:

Glyzinrezeptor

GlyRα3:

α3-Untereinheit des inhibitorischen Glyzinrezeptors

GlyT2:

Neuronaler Glyzintransporter 2

GlyT2-eGFP:

GlyT2-Promotor

GPCR:

G-Protein-gekoppelter Rezeptor

IOPr :

Nucleus olivaris principalis

KG:

Körpergewicht

KO:

knockout

mRNA:

„messenger ribonucleic acid“

NA:

Nucleus ambiguus

NaCl:

Natriumchlorid

NK-1R:

Neurokinin-1-Rezeptor

PBS:

„phosphate buffered saline“

PFA:

Paraformaldehyd

PKA:

Proteinkinase A

PNA:

N.-phrenicus-Aktivität

pre-BötC:

Pre-Bötzinger-Komplex

RT-PCR:

„reverse transcriptase polymerase chain reaction“

VRG:

Ventrale respiratorische Neuronen

ZNS:

Zentrales Nervensystem

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Authors and Affiliations

  1. Abteilung Neuro- und Sinnesphysiologie, Universität Göttingen, Humboldtallee 23, 37073, Göttingen, Deutschland

    T. Manzke, M. Niebert, U.R. Koch, A.-M. Bischoff, S. Hülsmann, E. Ponimaskin & D.W. Richter

  2. DFG Forschungszentrum für Molekulare Physiologie des Gehirns (CMPB), Göttingen, Deutschland

    T. Manzke, M. Niebert, S. Vogelgesang, S. Hülsmann, E. Ponimaskin & D.W. Richter

  3. Department of Pharmacology, The School of Pharmacy, London, UK

    A. Caley & R.J. Harvey

  4. Department of Neuroscience, Physiology & Pharmacology, University College London, London, UK

    A. Caley & T.G. Smart

  5. Institut für Pharmakologie und Molekulare Biotechnologie IPMB, Universität Heidelberg, Heidelberg, Deutschland

    U. Müller

Authors
  1. T. Manzke
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  2. M. Niebert
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  3. U.R. Koch
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  4. A. Caley
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  6. A.-M. Bischoff
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  7. S. Hülsmann
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  9. U. Müller
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  12. D.W. Richter
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Correspondence to T. Manzke.

Additional information

Dieser Beitrag basiert auf einer englischen Publikation: Manzke T, Niebert M, Koch UR et al (2010) Serotonin receptor 1A-modulated phosphorylation of glycine receptor α3 controls breathing in mice. J Clin Invest 120:4118–4128

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Manzke, T., Niebert, M., Koch, U. et al. Die von Serotoninrezeptor 1A modulierte Dephosphorylierung des Glyzinrezeptors α3. Schmerz 25, 272–281 (2011). https://doi.org/10.1007/s00482-011-1044-1

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