Abstract
Kv7 (“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 Kv7 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 Kv7 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.
Highlights
Kv7 channels, known as M-type, or KCNQ channels, are low-threshold voltage gated K+ channels first described almost 40 years ago as underlying the cholinergic slow excitatory postsynaptic potential in sympathetic neurons (Brown and Adams, 1980; Constanti and Brown, 1981)
Ethanol has been shown to reduce Kv7.2 trafficking to the membrane in neurons of the nucleus accumbens (NAc; McGuier et al, 2016), a region that is heavily innervated by the VTA and fundamental for reward and drug addiction (Weiss et al, 1993; Robinson and Berridge, 2003; Morales and Pickel, 2012)
Pharmacological M-current manipulation is only approved by the FDA for treatment of epilepsy, as mentioned above, RTG is off the market and its predecessor, flupertine (Szelenyi, 2013), has unacceptable liver toxicity (Puls et al, 2011; Michel et al, 2012)
Summary
Kv7 channels, known as M-type, or KCNQ channels, are low-threshold voltage gated K+ channels first described almost 40 years ago as underlying the cholinergic slow excitatory postsynaptic potential in sympathetic neurons (Brown and Adams, 1980; Constanti and Brown, 1981). The various elements of the injury-induced cascade of events are likely to further cross-activate each other resulting in the secondary injury often observed in TBI (Beez et al, 2017; Simon et al, 2017), SCI (Ahuja et al, 2017), and stroke (Hemphill et al, 2015; Beez et al, 2017) By initially preventing this cascade of events at the start, M-current augmentation should have long-lasting beneficial effects in these neurovascular injury events (Figure 1). Post-traumatic epileptogenesis entails a wide scope of regulatory plasticity from many different ion channels, including GABAA receptors, HCN channels, and Kv7 channels, which often provide inhibitory opposition in response to neuronal hyperexcitability
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