Gabapentin promotes inhibition by enhancing hyperpolarization-activated cation currents and spontaneous firing in hippocampal CA1 interneurons

Peng, Bi Wen; Justice, Jason A.; Zhang, Kun; Li, Jun-Xu; He, Xiao; Sánchez, Raúl Hernández

doi:10.1016/j.neulet.2011.02.045

Cited by 16 publications

(14 citation statements)

References 21 publications

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“…Quantitatively, the increase of I h was about 34% using 100 μM gabapentin. A similar effect was demonstrated also on hippocampal CA1 stratum oriens non-pyramidal neurons; interestingly, pretreatment with ZD7288 completely prevented the effect of the drug [202]. I h activating properties have been demonstrated also for lamotrigine, another anticonvulsant, unrelated to gabapentin either structurally or regarding the mechanism of antiepileptic activity.…”

Section: Substances That Have Been Shown To Modulate Hcn Channel Actimentioning

confidence: 70%

HCN Channels Modulators: The Need for Selectivity

Romanelli

Sartiani²,

Masi³

et al. 2016

CTMC

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Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular correlate of the hyperpolarization-activated current (I f /I h ), are membrane proteins which play an important role in several physiological processes and various pathological conditions. In the Sino Atrial Node (SAN) HCN4 is the target of ivabradine, a bradycardic agent that is, at the moment, the only drug which specifically blocks I f . Nevertheless, several other pharmacological agents have been shown to modulate HCN channels, a property that may contribute to their therapeutic activity and/or to their side effects.HCN channels are considered potential targets for developing drugs to treat several important pathologies, but a major issue in this field is the discovery of isoform-selective compounds, owing to the wide distribution of these proteins into the central and peripheral nervous systems, heart and other peripheral tissues. This survey is focused on the compounds that have been shown, or have been designed, to interact with HCN channels and on their binding sites, with the aim to summarize current knowledge and possibly to unveil useful information to design new potent and selective modulators.

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Section: Substances That Have Been Shown To Modulate Hcn Channel Actimentioning

confidence: 70%

HCN Channels Modulators: The Need for Selectivity

Romanelli

Sartiani²,

Masi³

et al. 2016

CTMC

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“…Conversely, gabapentin augmented in hippocampal and inhibitory interneurons, cells that highly express HCN1 and HCN2 (Peng et al, 2011;Surges et al, 2003). Thus, indirect modes of action of gabapentin may occur in vivo, as reported for Kv currents in rat DRG neurons (McClelland et al, 2004).…”

Section: Multiple Gabapentinoid Targets In Neurons -A Role For Kcnqs?mentioning

confidence: 89%

“…Gabapentin has also been found to augment KATP currents in rat hippocampal and human neocortical slices (but not incidentally, in rat DRG neurons) (Freiman et al, 2001), and to inhibit the hyperpolarization-activated, cyclic nucleotide-gated channel, HCN4, albeit not at clinically relevant drug concentrations (Tae et al, 2017). Conversely, gabapentin augmented in hippocampal and inhibitory interneurons, cells that highly express HCN1 and HCN2 (Peng et al, 2011;Surges et al, 2003). Thus, indirect modes of action of gabapentin may occur in vivo, as reported for Kv currents in rat DRG neurons (McClelland et al, 2004).…”

Section: Multiple Gabapentinoid Targets In Neurons -A Role For Kcnqs?mentioning

confidence: 99%

Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels

Manville

Abbott

2018

Mol Pharmacol

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IntroductionGabapentin (Neurontin) and pregabalin (Lyrica) are synthetic antiepileptic and antinociceptive gabapentinoid compounds originally designed as analogues of the neurotransmitter γ-aminobutyric acid (GABA), and both are in widespread clinical use (Calandre et al., 2016). However, the mechanisms of action of gabapentinoids, exemplified by gabapentin and pregabalin, are incompletely understood. [ 3 H]-gabapentin binding was first described in membrane fractions from rat brain homogenates, and the target protein identified as the α2-δ subunit of voltage-gated calcium (CaV) channels. The findings were later recapitulated using porcine brain tissue, heterologously expressed α2-δ, and also with pregabalin; binding was found to be exclusive to α2-δ1 and 2 isoforms (Brown and Gee, 1998; Field et al., 2006; Fuller-Bicer et al., 2009; Gee et al., This article has not been copyedited and formatted. The final version may differ from this version.Molecular Pharmacology Fast Forward. Published on as DOI: 10.1124 at ASPET Journals on April 27, 2019 molpharm.aspetjournals.org Downloaded from MOL #112953 4 1996). Gabapentin and pregabalin are generally considered inactive against canonical GABAA and GABAB receptors, despite their structural similarity to GABA (Ben-Menachem, 2004; Jensen et al., 2002; Lanneau et al., 2001;Stringer and Lorenzo, 1999;Taylor, 1997), although some investigators contend that there are some subtype-specific effects on GABAB receptors (Bertrand et al., 2003a;Ng et al., 2001;Parker et al., 2004). Binding of gabapentin and pregabalin to α2-δ is suggested to act therapeutically via impairment of Cav channel activity, thus reducing neuronal calcium currents (Stefani et al., 1998;Stefani et al., 2001), although others observed no evidence for gabapentin-induced changes in neuronal Cav activity (Rock et al., 1993;Schumacher et al., 1998).We recently made the unexpected discovery that GABA can activate voltage-gated potassium (Kv) channels composed of heteromeric assemblies of KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) poreforming α subunits (Manville et al., 2018). KCNQ (Kv7) channels comprise tetramers of α subunits, each containing six transmembrane (S) segments, organized into the voltage-sensing domain (VSD, S1-4) and the pore module (S5-6) ( Fig. 1 A, B). In vertebrate nervous systems, KCNQ2/3 (Kv7.2/3) heteromers are the primary molecular correlate of the M-current, a muscarinicinhibited Kv current essential for regulating excitability of a wide range of neurons throughout the nervous system (Brown and Adams, 1980;Marrion et al., 1989;Wang et al., 1998). We found that, like the anticonvulsant retigabine (Kim et al., 2015;Schenzer et al., 2005), GABA binds to a conserved tryptophan (W265) on KCNQ3 to activate KCNQ3 homomers and KCNQ2/3 heteromers (Manville et al., 2018) (Fig. 1B-D).Because of the structural similarities between gabapentinoids and GABA, and the known influence of the M-current in many of the disease states responsive to gabapentinoids (epilepsy, pain, anxiety, alcohol withdrawal) (Bla...

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“…In a recent study, topiramate was shown to reduce the hyperexcitability in the basolateral amygdala by selectively inhibiting GluK1 (GluR5) kainate receptors on interneurons, enhancing GABAergic transmission in interneuron-to-pyramidal cell synapses, and directly enhancing GABA A receptor-mediated inhibitory currents [78] . In addition, Peng et al [79,80] concluded that the AEDs gabapentin and lamotrigine increase the hyperpolarization-activated cation current (I-H) in CA1 interneurons by decreasing EPSC frequency or increasing IPSC frequency, similar to I-H in pyramidal neurons and I-H enhancement-increased interneuron excitability. Thus, these drugs indirectly increase the spontaneous inhibition of pyramidal neurons.…”

Section: Drug Therapymentioning

confidence: 99%

Dysfunction of hippocampal interneurons in epilepsy

Liu

et al. 2014

Neurosci. Bull.

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Gamma-amino-butyric acid (GABA)-containing interneurons are crucial to both development and function of the brain. Down-regulation of GABAergic inhibition may result in the generation of epileptiform activity. Loss, axonal sprouting, and dysfunction of interneurons are regarded as mechanisms involved in epileptogenesis. Recent evidence suggests that network connectivity and the properties of interneurons are responsible for excitatory-inhibitory neuronal circuits. The balance between excitation and inhibition in CA1 neuronal circuitry is considerably altered during epileptic changes. This review discusses interneuron diversity, the causes of interneuron dysfunction in epilepsy, and the possibility of using GABAergic neuronal progenitors for the treatment of epilepsy.

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Gabapentin promotes inhibition by enhancing hyperpolarization-activated cation currents and spontaneous firing in hippocampal CA1 interneurons

Cited by 16 publications

References 21 publications

HCN Channels Modulators: The Need for Selectivity

HCN Channels Modulators: The Need for Selectivity

Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels

Dysfunction of hippocampal interneurons in epilepsy

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