Gabapentin Modulates HCN4 Channel Voltage-Dependence

Tae, Han Shen; Smith, Kelly M.; Phillips, A. Marie; Boyle, Kieran A.; Li, Melody; Forster, Ian C.; Hatch, Robert J.; Richardson, Robert J.; Hughes, David I.; Graham, Brett A.; Petrou, Steven; Reid, Christopher A.

doi:10.3389/fphar.2017.00554

Cited by 30 publications

(23 citation statements)

References 52 publications

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“…The final version may differ from this version. 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).…”

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

Molecular Pharmacology

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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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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

Molecular Pharmacology

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“…This would predict additional mechanisms of Drugs for Neuropathic Pain gabapentinoid effectiveness. For example, gabapentin has been reported to shift the voltage dependence of HCN4 channels to more negative potentials (Tae et al, 2017), but may increase hyperpolarization-activated cation current in hippocampal neurons (Surges et al, 2003). It has also been reported to interact with NMDA and AMPA receptors, as well as K ATP channels (Cheng and Chiou, 2006).…”

mentioning

confidence: 99%

Etiology and Pharmacology of Neuropathic Pain

Alles¹,

Smith²

2018

Pharmacological Reviews

314

251

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“…Most notably, both excitatory and inhibitory PV-neurons in the LTMR-RZ exhibit tonic firing and the voltage sag (a slowly developing depolarization during hyperpolarizing current injection), which is generated by the activation of I h upon hyperpolarization [ 28 ]. Although Tae et al (2017) recorded I h in putative inhibitory neurons that expressed GFP driven by the PV promoter, they also demonstrated that Pax2 (a marker of inhibitory neurons) did not colocalize with HCN4 [ 35 ]. Furthermore, we found that almost all HCN4-IR neurons lacked fluorescent proteins in VGAT-Venus or GAD67-GFP mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…For the same rationale, HCN channels may antagonize the hyperpolarization of PKCγ-IR interneurons induced by the activity of inhibitory interneurons. HCN channels expressed in the spinal cord, as well as in the PNS, may be potential therapeutic targets of allodynia [ 35 , 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Expression of the pacemaker channel HCN4 in excitatory interneurons in the dorsal horn of the murine spinal cord

et al. 2020

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In the central nervous system, hyperpolarization-activated, cyclic nucleotide-gated (HCN1–4) channels have been implicated in neuronal excitability and synaptic transmission. It has been reported that HCN channels are expressed in the spinal cord, but knowledge about their physiological roles, as well as their distribution profiles, appear to be limited. We generated a transgenic mouse in which the expression of HCN4 can be reversibly knocked down using a genetic tetracycline-dependent switch and conducted genetically validated immunohistochemistry for HCN4. We found that the somata of HCN4-immunoreactive (IR) cells were largely restricted to the ventral part of the inner lamina II and lamina III. Many of these cells were either parvalbumin- or protein kinase Cγ (PKCγ)-IR. By using two different mouse strains in which reporters are expressed only in inhibitory neurons, we determined that the vast majority of HCN4-IR cells were excitatory neurons. Mechanical and thermal noxious stimulation did not induce c-Fos expression in HCN4-IR cells. PKCγ-neurons in this area are known to play a pivotal role in the polysynaptic pathway between tactile afferents and nociceptive projection cells that contributes to tactile allodynia. Therefore, pharmacological and/or genetic manipulations of HCN4-expressing neurons may provide a novel therapeutic strategy for the pain relief of tactile allodynia.

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Gabapentin Modulates HCN4 Channel Voltage-Dependence

Cited by 30 publications

References 52 publications

Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels

Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels

Etiology and Pharmacology of Neuropathic Pain

Expression of the pacemaker channel HCN4 in excitatory interneurons in the dorsal horn of the murine spinal cord

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