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Molecular mechanisms of interaction between the neuroprotective substance riluzole and GABAA-receptors

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Abstract

The antiepileptic drug riluzole is used as a therapeutic agent in amyotrophic lateral sclerosis due to its neuroprotective effects. Besides presynaptic inhibition of GABAergic and preferentially glutamatergic transmission, it also potentiates postsynaptic GABAA-receptor function. We investigated the postsynaptic effects of riluzole on GABAA-receptor channels by use of the patch-clamp technique. Recombinant α1β2γ2s and α1β2 GABAA receptors were expressed in HEK 293 cells by transient transfection. Pulses of GABA were applied in combination with different concentrations of riluzole to whole cell or outside-out patches with either α1β2γ2s or α1β2 GABAA-receptor channels. Co-application of riluzole led to a slight decrease of absolute peak current amplitudes and steady-state currents in prolonged presence of GABA at saturating concentrations. In the presence of riluzole, enhancement of current amplitudes was observed with lower concentrations of GABA at α1β2γ2s receptors and to a lower extent also at α1β2 receptors. Thus, the potentiating effect of riluzole was shown to be not abolished in the absence of the γ2s-subunit. A further prominent effect of riluzole was a highly significant acceleration of the time course of current decay, most probably pointing to an open-channel block-like mechanism of action. As both receptor subtypes were affected similarly by the block, it could be concluded that the respective binding sites should be assumed within a region of high sequence homology like it is given for the channel-lining M2 domain of GABAA-receptor subunits. In conclusion, three different molecular mechanisms of interaction of the neuroprotective compound riluzole were observed at two different subtypes of GABAA receptor channels. The results further point to the impact of the inhibitory as well as the excitatory synaptic activity as a pharmacological target to counteract chronic excitotoxicity and reveal molecular mechanisms of action of the only one neuroprotective drug in current clinical use in patients suffering from amyotrophic lateral sclerosis.

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Abbreviations

ALS:

amyotrophic lateral sclerosis

FCS:

fetal calf serum

GABA:

γ-aminobutyric acid

HEK cells:

human embryonic kidney cells

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Acknowledgements

This study was supported by a grant of the Deutsche Forschungsgemeinschaft (DFG Bu 938/8-2 to JB and KK) and by support of the Medizinische Hochschule Hannover to KJ (HiLF). Excellent technical support was provided by U. Jensen and A. Niesel.

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Authors and Affiliations

  1. Department of Neurology, Medical School Hannover, Carl-Neuberg-Str.1, Hannover, 30625, Germany

    K. Jahn, F. Schlesinger, L. J. Jin, R. Dengler, J. Bufler & K. Krampfl

  2. Center of Systems Neuroscience, Hannover, Germany

    K. Jahn, F. Schlesinger, R. Dengler, J. Bufler & K. Krampfl

  3. Department of Neurology, Tongji Hospital, Tongji University, Shanghai, China

    L. J. Jin

Authors
  1. K. Jahn
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  2. F. Schlesinger
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  3. L. J. Jin
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  4. R. Dengler
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  5. J. Bufler
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  6. K. Krampfl
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Correspondence to K. Jahn.

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Jahn, K., Schlesinger, F., Jin, L.J. et al. Molecular mechanisms of interaction between the neuroprotective substance riluzole and GABAA-receptors. Naunyn-Schmied Arch Pharmacol 378, 53–63 (2008). https://doi.org/10.1007/s00210-008-0290-y

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  • DOI: https://doi.org/10.1007/s00210-008-0290-y

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