Kv7 channels: interaction with dopaminergic and serotonergic neurotransmission in the CNS

Abstract

Neuronal Kv7 channels (also termed KCNQ channels) are the molecular correlate of the M-current. The Kv7 channels activate at rather negative membrane potentials (≤ 60 mV), thereby 'fine-tuning' the resting membrane potential. The Kv7 channels are widely expressed in the brain with the Kv7.2, Kv7.3 and Kv7.5 channels being the most abundant. The Kv7.4 subunit has the most restricted brain regional expression being present in discrete nuclei of brainstem only. Kv7 channels are expressed at different subcellular locations, being on both somatodendritic, axonal and terminal sites. This complex subcellular distribution of Kv7 channels enables them to participate in both pre-and postsynaptic modulation of basal and stimulated excitatory neurotransmission. Activation of neuronal Kv7 channels limits repetitive firing thereby potentially limiting the generation of long bursts, with subsequent inhibition of monoaminergic neurotransmitter release. In this review, we focus on the influence of Kv7 channels on dopaminergic and serotonergic neurotransmission. The data suggest a novel action of Kv7 channel openers which could translate into having therapeutic value in the treatment of disease states characterized by overactivity of dopaminergic (e.g. schizophrenia and drug abuse) and serotonergic neurotransmission (e.g. anxiety).

Cardiovascular KCNQ (Kv7) Potassium Channels: Physiological Regulators and New Targets for Therapeutic Intervention

“…Kv7.4 channels in particular have been implicated in the control of somatodendritic neuronal excitability in monoaminergic neurons (Hansen et al, 2008). This finding has suggested a possible use of Kv7.4 channel openers in the treatment of disease states characterized by dopaminergic or serotonergic overactivity, including schizophrenia, drug abuse, and anxiety (Hansen et al, 2008). It is not clear to what extent modulation of these neurotransmitter systems might also influence the cardiovascular system.…”

“…On the other hand, Kv7 channel openers effectively inhibit neurotransmitter release, which may account for a resulting decrease in dopaminergic and serotonergic activity in the central nervous system (Hansen et al, 2008). Kv7.4 channels in particular have been implicated in the control of somatodendritic neuronal excitability in monoaminergic neurons (Hansen et al, 2008). This finding has suggested a possible use of Kv7.4 channel openers in the treatment of disease states characterized by dopaminergic or serotonergic overactivity, including schizophrenia, drug abuse, and anxiety (Hansen et al, 2008).…”

“…There is also evidence that suppression of Kv7 currents can enhance neurotransmitter release presynaptically (Hernandez et al, 2008). On the other hand, Kv7 channel openers effectively inhibit neurotransmitter release, which may account for a resulting decrease in dopaminergic and serotonergic activity in the central nervous system (Hansen et al, 2008). Kv7.4 channels in particular have been implicated in the control of somatodendritic neuronal excitability in monoaminergic neurons (Hansen et al, 2008).…”

Chronic Intermittent Ethanol Exposure Enhances the Excitability and Synaptic Plasticity of Lateral Orbitofrontal Cortex Neurons and Induces a Tolerance to the Acute Inhibitory Actions of Ethanol

“…Several of these studies also reported decreases in SK channel function (Hopf et al, 2007(Hopf et al, , 2010Mulholland et al, 2011;Padula et al, 2015), suggesting that these channels are particularly sensitive to chronic ethanol exposure. Although downregulation of SK channel function would be expected to alter AP firing, AHPs are also generated by KCNQ channels that mediate M-currents and HCN channels that underlie the I H current (Gu et al, 2005;Hansen et al, 2008). Chronic ethanol exposure has been reported to alter the I H current in VTA DA neurons (Okamoto et al, 2006), whereas changes in KCNQ expression or function following chronic ethanol exposure are less well studied.…”

Subtype-Selective Activation of Kv7 Channels by AaTXKβ(2–64), a Novel Toxin Variant from theAndroctonus australisScorpion Venom

“…K v 7.4-selective openers may improve hearing loss (Leitner et al, 2012), systemic or pulmonary arterial hypertension (Mani and Byron, 2011), urinary incontinence (Rode et al, 2010), gastrointestinal (Jepps et al, 2009;Ipavec et al, 2011) and neuropsychiatric (Hansen et al, 2008) diseases, and skeletal muscle disorders (Iannotti et al, 2010(Iannotti et al, , 2013. However, most of available synthetic compounds discriminated poorly among K v 7 channels formed by distinct combinations of K v 7.2-5 subunits (Xiong et al, 2008).…”