Regulation of neural KCNQ channels: signalling pathways, structural motifs and functional implications

Abstract

Neural M-type (KCNQ/Kv7) K + channels control somatic excitability, bursting and neurotransmitter release throughout the nervous system. Their activity is regulated by multiple signalling pathways. In superior cervical ganglion sympathetic neurons, muscarinic M 1 , angiotensin II AT 1 , bradykinin B 2 and purinergic P2Y agonists suppress M current (I M ). Probes of PLC activity show agonists of all four receptors to induce robust PIP 2 hydrolysis. We have grouped these receptors into two related modes of action. One mode involves depletion of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) in the membrane, whose interaction with the channels is thought necessary for their function. The other involves IP 3 -mediated intracellular Ca 2+ signals that stimulate PIP 2 synthesis, preventing its depletion, and suppress I M via calmodulin. Carbon-fibre amperometry can evaluate the effect of M channel activity on release of neurotransmitter. Consistent with the dominant role of M current in control of neuronal discharge, M channel openers, or blockers, reduced or augmented the evoked release of noradrenaline neurotransmitter from superior cervical ganglion (SCG) neurons, respectively. We seek to localize the subdomains on the channels critical to their regulation by PIP 2 . Based on single-channel recordings from chimeras between high-PIP 2 affinity KCNQ3 and low-PIP 2 affinity KCNQ4 channels, we focus on a 57-residue domain within the carboxy-terminus that is a possible PIP 2 binding site. Homology modelling of this domain using the published structure of IRK1 channels as a template predicts a structure very similar to an analogous region in IRK1 channels, and shows a cluster of basic residues in the KCNQ2 domain to correspond to those implicated in PIP 2 regulation of Kir channels. We discuss some important issues dealing with these topics.

Differential Protein Kinase C-dependent Modulation of Kv7.4 and Kv7.5 Subunits of Vascular Kv7 Channels

“…Several mechanisms previously described for agonist-induced suppression of neuronal M-currents could potentially operate in vascular myocytes (e.g. depletion of plasma membrane phosphatidylinositol 4,5-bisphosphate (36 -40), or elevation of cytosolic [Ca 2ϩ ]) (16,41). Our previous findings, however, strongly support involvement of PKC, a less commonly proposed regulator of M-currents (42,43), in the suppression of endogenous Kv7 currents by physiologically relevant concentrations of AVP.…”

“…Kv7 voltage-activated potassium channels are expressed in many excitable cell types, including neurons, cardiac, skeletal, vascular, and visceral myocytes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) where they function to stabilize resting membrane potential and restrict cellular excitability (6,16). The five members of the Kv7 family (Kv7.1-Kv7.5) are encoded by five mammalian genes (KCNQ1-5), and the individual gene products assemble as homomeric or heteromeric tetramers to form functional channels (17).…”

Dynamic PIP 2 interactions with voltage sensor elements contribute to KCNQ2 channel gating

“…Structural studies on Kir channels (1,2,5) demonstrated that PIP 2 directly interacts with the channels. Subsequent studies supported that PIP 2 also interacts directly with voltage-gated potassium (Kv) channels (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Several positive residues that may be critical for PIP 2 activity have been identified (7,11,18,(20)(21)(22)(23)(24).…”

Intracellular calcium level is an important factor influencing ion channel modulations by PLC-coupled metabotropic receptors in hippocampal neurons

“…The PLCβ enzymes play critical roles in neural functions, and PLCβ1-and PLCβ4-knockout mice develop epilepsy and ataxia, respectively (Kim et al, 1997). The G q/11 -coupled receptor-PLCβ signaling pathways contribute to neuronal functions through multiple second messengers that cause modulation of ion channels (Anwyl, 1999;Hernandez et al, 2008;Hughes et al, 2007;Suh and Hille, 2005), Ca 2+ release from internal stores (Ross et al, 2005), endocannabinoid release (Kano et al, 2009) and activation of enzymes (Amadio et al, 2006;Delmas et al, 2004). Understanding how these signaling pathways are regulated will undoubtedly lead to a better understanding of their roles in brain functions.…”