Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels

Abstract

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...

KCNQ/M-channels regulate mouse vagal bronchopulmonary C-fiber excitability and cough sensitivity

“…If these findings are also observed in humans, the M-channel would be a rational therapeutic target for inflammatory airway diseases. In support of this idea, a recent study has shown that gabapentin, a neuromodulator previously found to be effective for treatment of refractory chronic cough in patients (61), potently activates M-channels composed of KCNQ3, KCNQ5 homomers, or KCNQ2/3 heteromers (62). Moreover, airway smooth muscle cells also express functional KCNQ/K v 7 channels, and activating these channels by flupirtine or retigabine has been shown to attenuate the histamine-induced constriction of human airways (63) and relax muscarinic-evoked airway contraction in rodents (64,65).…”

Long noncoding RNA GAS5 silencing inhibits the expression of KCNQ3 by sponging miR‐135a‐5p to prevent the progression of epilepsy

“…The results obtained revealed that injection of either Lv-shGAS5 or Lv-miR-135a-5p significantly prolonged the epileptic latency and reduced the frequency of seizures. Although the implications of KCNQ3 and potassium channels in the pathogenesis of epilepsy have been illustrated in many studies, [35][36][37] the antiepileptic drugs dealing with potassium channels are still under investigated. This study highlighted a novel molecule mechanism that Lv-miR-135a-5p and Lv-shGAS5 are able to inhibit KCNQ3 expression in the rat models of epileptic seizure (Figure 4), indicating that downregulation of lncRNA GAS5 can decrease KCNQ3 through sponging miR-135a-5p to prolong latent period and to reduce seizure frequency.…”

Cilantro leaf harbors a potent potassium channel–activating anticonvulsant

“…Voltage-gated potassium (Kv) channels within the Kv channel subfamily Q (KCNQ), also termed the Kv7 subfamily, are sensitive to activation by a range of small molecules, including synthetic drugs, neurotransmitters, and metabolites (9)(10)(11)(12)(13). Kv channels, including the 5 isoforms within the KCNQ (Kv7) subfamily, are composed of tetramers of pore-forming (a) subunits, each consisting of 6 transmembrane segments (S): S1-4 comprise the voltage-sensing domain (VSD), and S5-6 comprise the pore module ( Fig.…”