Pharmacological disruption of calcium channel trafficking by the 2 ligand gabapentin

Laboratory for Cellular and Molecular Neuroscience, Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 04/2008; 105(9):3628-33. DOI: 10.1073/pnas.0708930105
Source: PubMed


The mechanism of action of the antiepileptic and antinociceptive drugs of the gabapentinoid family has remained poorly understood. Gabapentin (GBP) binds to an exofacial epitope of the alpha(2)delta-1 and alpha(2)delta-2 auxiliary subunits of voltage-gated calcium channels, but acute inhibition of calcium currents by GBP is either very minor or absent. We formulated the hypothesis that GBP impairs the ability of alpha(2)delta subunits to enhance voltage-gated Ca(2+)channel plasma membrane density by means of an effect on trafficking. Our results conclusively demonstrate that GBP inhibits calcium currents, mimicking a lack of alpha(2)delta only when applied chronically, but not acutely, both in heterologous expression systems and in dorsal root-ganglion neurons. GBP acts primarily at an intracellular location, requiring uptake, because the effect of chronically applied GBP is blocked by an inhibitor of the system-L neutral amino acid transporters and enhanced by coexpression of a transporter. However, it is mediated by alpha(2)delta subunits, being prevented by mutations in either alpha(2)delta-1 or alpha(2)delta-2 that abolish GBP binding, and is not observed for alpha(2)delta-3, which does not bind GBP. Furthermore, the trafficking of alpha(2)delta-2 and Ca(V)2 channels is disrupted both by GBP and by the mutation in alpha(2)delta-2, which prevents GBP binding, and we find that GBP reduces cell-surface expression of alpha(2)delta-2 and Ca(V)2.1 subunits. Our evidence indicates that GBP may act chronically by displacing an endogenous ligand that is normally a positive modulator of alpha(2)delta subunit function, thereby impairing the trafficking function of the alpha(2)delta subunits to which it binds.

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Available from: Jörg Striessnig
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    • "These compounds are useful in the treatment of a number of disorders, including epilepsy, but their modes of action are nonselective , and therefore, conclusions regarding the effects on GABA, particularly synaptic, are difficult to draw. The activity of these anticonvulsants include, but are not limited to, sodium and calcium channel modulation, mitochondrial neuroprotection, manipulation of the equilibrium with other neurotransmitters , and enzymatic induction or inhibition (Hendrich et al., 2008; Kudin et al., 2004; Micheva et al., 2006; Petroff et al., 1999a; Rogawski, 2006). More selective compounds, which modulate GABA directly, provide more pertinent tests of MRS sensitivity . "
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    • "These findings fit nicely with previous studies showing that the GABA-like antiepileptic drugs Gabapentin and Pregabalin bind α 2 δ-1 and α 2 δ-2 (Gee et al., 1996; Wang et al., 1999; Bian et al., 2006; Field et al., 2006). Although some reports indicate that these drugs produce acute inhibition of calcium currents (Stefani et al., 1998; Martin et al., 2002), the prevailing view is that the pharmacological action involves inhibition of the forward trafficking of Ca V 2.1 and Ca V 2.2 following chronic exposure (Kang et al., 2002; Vega-Hernandez and Felix, 2002; Hendrich et al., 2008). Binding of Gabapentin to α 2 δ appears to disrupt Rab11-dependent recycling from late endosomes, preventing the channel complex from returning to the plasma membrane (Tran-Van-Minh and Dolphin, 2010). "
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    • "It is likely that in neurons a 2 d subunits have multiple effects on calcium channel distribution, both associated with long-range calcium channel trafficking from their site of synthesis in the soma to their mainly presynaptic localization in nerve terminals (Bauer et al., 2009), and also local effects on calcium channel localization in membrane micro-domains such as the active zone and in lipid rafts (Davies et al., 2006; Hoppa et al., 2012), as well as influencing the recycling of calcium channels to the plasma membrane (Tran-Van- Minh and Dolphin, 2010). Furthermore, we have found that the gabapentinoid drugs have an inhibitory effect on calcium currents when applied over longer time periods, in cultured cells and neurons (Hendrich et al., 2008; Tran-Van-Minh and Dolphin, 2010), which we infer is by inhibiting the trafficking of the a 2 d subunits (Hendrich et al., 2008; Bauer et al., 2010; Tran-Van-Minh and Dolphin, 2010). We also observed in vivo that there was less upregulation of a 2 d-1 in nerve terminal zones, after the induction of somatosensory nerve injury when it was combined with chronic pregabalin treatment (Bauer et al., 2009), which might be an effect on long range axonal trafficking, or on lifetime of the protein and its local recycling at presynaptic terminals. "
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