Modulation of Kv7 channels and excitability in the brain

Abstract

Neuronal Kv7 channels underlie a voltage-gated non-inactivating potassium current known as the M-current. Due to its particular characteristics, Kv7 channels show pronounced control over the excitability of neurons. We will discuss various factors that have been shown to drastically alter the activity of this channel such as protein and phospholipid interactions, phosphorylation, calcium, and numerous neurotransmitters. Kv7 channels locate to key areas for the control of action potential initiation and propagation. Moreover, we will explore the dynamic surface expression of the channel modulated by neurotransmitters and neural activity. We will also focus on known principle functions of neural Kv7 channels: control of resting membrane potential and spiking threshold, setting the firing frequency, afterhyperpolarization after burst firing, theta resonance, and transient hyperexcitability from neurotransmitter-induced suppression of the M-current. Finally, we will discuss the contribution of altered Kv7 activity to pathologies such as epilepsy and cognitive deficits.

Keywords: Channel trafficking; Epilepsy; Excitability; KCNQ; Kv7; M-current.

Fig. 1

Summary of Kv7 channel family and their binding proteins. a Subtypes of Kv7 channel family and their expression pattern. b Summary of subunit composition with Kv7.2. 7.3 and 7.5 subunits, which is widely observed in neurons. c Schematic summary of signaling proteins that are tethered to Kv7.2 subunit. PP1 protein phosphatase 1, CK2 CK2 protein kinse, CaM calmodulin, PKC protein kinse C, PP2B protein phosphatase 2B, PKA protein kinse A. d Schematic summary of accessory proteins for Kv7.2 subunit. Navβ1 sodium channel β subunit 1, BACE1 β-site amyloid precursor protein cleaving enzyme 1. e Schematic summary of identified regulator proteins for Kv7.2 channel trafficking. CRMP2 collapsin response mediator protein 2

Fig. 2

Schematic summary of molecular configuration of Kv7 channel and its modulation modified from Ref [29]. a Activation of Gq/11 coupled receptor induces depletion of PIP2 as well as activation of PKC, which phosphorylates Kv7 channel leading to dissociation of CaM and unstabilized PIP2 interaction. b Increase in cytosolic calcium induces change in CaM conformation, and configuration between CaM and Kv7 channel, which leads to unstabilized PIP2 interaction

Fig. 3

Summary of physiological relevance of neuronal Kv7 channel and its modulation