Pharmacological Manipulation of Kv7 Channels as a New Therapeutic Tool for Multiple Brain Disorders

Abstract

K v 7 ("M-type," KCNQ) K + currents, play dominant roles in controlling neuronal excitability. They act as a "brake" against hyperexcitable states in the central and peripheral nervous systems. Pharmacological augmentation of M current has been developed for controlling epileptic seizures, although current pharmacological tools are uneven in practical usefulness. Lately, however, M-current "opener" compounds have been suggested to be efficacious in preventing brain damage after multiple types of insults/diseases, such as stroke, traumatic brain injury, drug addiction and mood disorders. In this review, we will discuss what is known to date on these efforts and identify gaps in our knowledge regarding the link between M current and therapeutic potential for these disorders. We will outline the preclinical experiments that are yet to be performed to demonstrate the likelihood of success of this approach in human trials. Finally, we also address multiple pharmacological tools available to manipulate different K v 7 subunits and the relevant evidence for translational application in the clinical use for disorders of the central nervous system and multiple types of brain insults. We feel there to be great potential for manipulation of K v 7 channels as a novel therapeutic mode of intervention in the clinic, and that the paucity of existing therapies obligates us to perform further research, so that patients can soon benefit from such therapeutic approaches.

Cannabidiol activates neuronal Kv7 channels

“…Kv7 channel-mediated M-current plays a major role in controlling the excitability of many types of neurons, including neocortical pyramidal neurons ( Barrese et al, 2018 ; Brown and Passmore, 2009 ; Gunthorpe et al, 2012 ; Vigil et al, 2020 ; Jepps et al, 2021 ). Enhancement of M-current is a clinically proven mechanism of antiepileptic action, as demonstrated by the clinical efficacy of retigabine, an antiepileptic drug that acts by enhancement of current through Kv7 channels ( Wickenden et al, 2000 ; Tatulian et al, 2001 ; Gunthorpe et al, 2012 ; Sills and Rogawski, 2020 ).…”

“…Such agents include endogenous compounds like GABA ( Manville et al, 2018b ), the ketone body β-hydroxybutyrate ( Manville et al, 2020 ), and arachidonic acid metabolites and derivatives ( Schweitzer et al, 1990 ; Schweitzer et al, 1993 ; Larsson et al, 2020a ; Larsson et al, 2020b ), as well as a variety of natural products including cilantro ( Manville and Abbott, 2019 ). Further development of Kv7.2/7.3 enhancers for treating epilepsy and other neuronal disorders seems promising ( Maljevic and Lerche, 2014 ; Vigil et al, 2020 ), especially because retigabine has been withdrawn from clinical use because of a number of off-target side effects ( Brickel et al, 2020 ). Compared to other compounds recently found to enhance Kv7.2/7.3 channels, CBD has the distinction of having already been successfully used in multiple epilepsy clinical trials.…”

Dopamine drives neuronal excitability via KCNQ channel phosphorylation for reward behavior

“…KCNQ modulation as a key target for drug discovery in neurological and psychiatric diseases KCNQ modulation may be involved in the pathophysiology of not only epilepsy but also several lines of psychiatric diseases, including drug addiction and major depression (Cooper and Jan, 2003;Vigil et al, 2020;Huang et al, 2021). Drug addiction and major depression are clinically characterized by dysfunctional circuit activity in rewarding stimuli.…”

Glycogen Synthase Kinase 3: Ion Channels, Plasticity, and Diseases

“…This finding implicates FGF14 as an organizer of channel localization in the AIS and suggests possible GSK3β/FGF14-dependent modulation of K v 7.2 conductance [213]. Since M-channel dysfunction has been linked to schizophrenia [214], epilepsy [215][216][217], and bipolar disorder [210,218,219], neuronal hyperexcitability resulting from impaired GSK3β-dependent M-channel dysfunction is likely a common denominator in several neurological and psychiatric illnesses [220][221][222][223].…”