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Lack of positive allosteric modulation of mutated α1S267I glycine receptors by cannabinoids

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Abstract

Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. Ajulemic acid and HU210 are non-psychotropic, synthetic cannabinoids. Cannabidiol is a non-psychotropic plant constituent of cannabis sativa. There are hints that non-cannabinoid receptor mechanisms of these cannabinoids might be mediated via glycine receptors. In this study, we investigated the impact of the amino acid residue serine at position 267 on the glycine-modulatory effects of ajulemic acid, cannabidiol and HU210. Mutated α1S267I glycine receptors transiently expressed in HEK293 cells were studied by utilising the whole-cell clamp technique. The mutation of the α1 subunit TM2 serine residue to isoleucine abolished the co-activation and the direct activation of the glycine receptor by the investigated cannabinoids. The nature of the TM2 (267) residue of the glycine α1 subunit is crucial for the glycine-modulatory effect of ajulemic acid, cannabidiol and HU210. An investigation of the impact of such mutations on the in vivo interaction of cannabinoids with glycine receptors should permit a better understanding of the molecular determinants of action of cannabinoids.

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Acknowledgement

We are grateful to Prof. Jeremy J. Lambert, Neuroscience Institute, University of Dundee, UK, for providing us with mutated α1 cDNA; J. Kilian and A. Niesel, Department of Neurology, Hannover, for technical support and Prof. Sumner Burstein, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, USA, for his kind supply of AJA.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Clinic for Anaesthesia and Critical Care Medicine; OE 8050, Hannover Medical School, Carl-Neuberg-Str. 1, 30623, Hannover, Germany

    Nilufar Foadi, Reyhan Demir, Vanessa Buchholz, Jeanne de la Roche, Matthias Karst & Jörg Ahrens

  2. Department of Neurology and Neurophysiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30623, Hannover, Germany

    Reinhard Dengler

  3. Division of Clinical Sciences, The University of Liverpool, Daulby Street, Liverpool, L69 3GA, UK

    Martin Leuwer

  4. Clinic for Anaesthesia, St. Elisabeth Krankenhaus Dorsten, Pfarrer-Schmitz-Str. 1, Dorsten, Germany

    Gertrud Haeseler

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  1. Nilufar Foadi
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  2. Martin Leuwer
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Correspondence to Jörg Ahrens.

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Foadi, N., Leuwer, M., Demir, R. et al. Lack of positive allosteric modulation of mutated α1S267I glycine receptors by cannabinoids. Naunyn-Schmied Arch Pharmacol 381, 477–482 (2010). https://doi.org/10.1007/s00210-010-0506-9

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  • DOI: https://doi.org/10.1007/s00210-010-0506-9

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