New insights in endogenous modulation of ligand-gated ion channels: Histamine is an inverse agonist at strychnine sensitive glycine receptors

Histamine is involved in many physiological functions in the periphery and is an important neurotransmitter in the brain. It acts on metabotropic H1–H4 receptors mediating vasodilatation, bronchoconstriction and stimulation of gastric acid secretion. In the brain histamine is produced by neurons in...

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Bibliographic Details
Published in:European journal of pharmacology 2013-06, Vol.710 (1-3), p.59-66
Main Authors: Kletke, Olaf, Sergeeva, Olga A., Lorenz, Philipp, Oberland, Sonja, Meier, Jochen C., Hatt, Hanns, Gisselmann, Günter
Format: Article
Language:English
Subjects:
agonists
Animals
binding sites
brain
bronchoconstriction
Competitive antagonist
DNA, Complementary - genetics
dose response
electrodes
Endogenous modulator
gastric acid
Glycine
Histamine
Histamine - pharmacology
Humans
Hypothalamus - cytology
inhibitory concentration 50
ion channels
Ligand-gated ion channel
Male
Mice, Inbred C57BL
Modulation
neurons
Neurons - drug effects
Neurons - metabolism
oocytes
Oocytes - drug effects
Oocytes - metabolism
patch-clamp technique
pharmacology
Protein Subunits - antagonists & inhibitors
Protein Subunits - genetics
Protein Subunits - metabolism
Rats
receptors
Receptors, Glycine - antagonists & inhibitors
Receptors, Glycine - genetics
Receptors, Glycine - metabolism
Recombinant Proteins - metabolism
secretion
strychnine
vasodilation
Xenopus laevis
Xenopus laevis - genetics
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Summary:Histamine is involved in many physiological functions in the periphery and is an important neurotransmitter in the brain. It acts on metabotropic H1–H4 receptors mediating vasodilatation, bronchoconstriction and stimulation of gastric acid secretion. In the brain histamine is produced by neurons in the tuberomamillary nucleus (TMN), which controls arousal. Histamine is also a positive modulator of the inhibitory Cys-loop ligand-gated ion channel GABAA. We investigated now its effect on the second member of inhibitory Cys-loop ligand-gated ion channels, the strychnine sensitive glycine receptor. We expressed different human and rat glycine receptor subunits in Xenopus laevis oocytes and characterized the effect of histamine using the two electrode voltage clamp technique. Furthermore we investigated native glycine receptors in hypothalamic neurons using the patch-clamp technique. Histamine inhibited α1β glycine receptors with an IC50 of 5.2±0.3mM. In presence of 10mM histamine the glycine dose–response curve was shifted, increasing the EC50 for glycine from 25.5±1.4μM to 42.4±2.3μM. In addition, histamine blocked the spontaneous activity of RNA-edited α3β glycine receptors. Histamine inhibited glycine receptors expressed in hypothalamic TMN neurons with an IC50 of 4.6±0.3mM. Our results give strong evidence that histamine is acting on the same binding site as glycine, being an inverse agonist that competitively antagonizes glycine receptors. Thus, we revealed histamine as an endogenous modulator of glycine receptors.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2013.04.002