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

Ciria C. Hernandez, Oleg Zaika, Gleb P. Tolstykh, Mark S Shapiro

Research output: Contribution to journalArticle

105 Citations (Scopus)

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 M1, angiotensin II AT1, bradykinin B2 and purinergic P2Y agonists suppress M current (IM). Probes of PLC activity show agonists of all four receptors to induce robust PIP2 hydrolysis. We have grouped these receptors into two related modes of action. One mode involves depletion of phosphatidylinositol 4,5-bisphosphate (PIP2) in the membrane, whose interaction with the channels is thought necessary for their function. The other involves IP3 -mediated intracellular Ca2+ signals that stimulate PIP2 synthesis, preventing its depletion, and suppress IM 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 PIP2. Based on single-channel recordings from chimeras between high-PIP2 affinity KCNQ3 and low-PIP2 affinity KCNQ4 channels, we focus on a 57-residue domain within the carboxy-terminus that is a possible PIP2 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 PIP2 regulation of Kir channels. We discuss some important issues dealing with these topics.

Original languageEnglish (US)
Pages (from-to)1811-1821
Number of pages11
JournalJournal of Physiology
Volume586
Issue number7
DOIs
StatePublished - Apr 1 2008

Fingerprint

Inwardly Rectifying Potassium Channel
Neurotransmitter Agents
Superior Cervical Ganglion
Purinergic Agonists
Neurons
Bradykinin
Calmodulin
Phosphatidylinositols
Angiotensin II
Cholinergic Agents
Nervous System
Norepinephrine
Hydrolysis
Binding Sites
Membranes
carbon fiber

ASJC Scopus subject areas

  • Physiology
  • Medicine(all)

Cite this

Regulation of neural KCNQ channels : Signalling pathways, structural motifs and functional implications. / Hernandez, Ciria C.; Zaika, Oleg; Tolstykh, Gleb P.; Shapiro, Mark S.

In: Journal of Physiology, Vol. 586, No. 7, 01.04.2008, p. 1811-1821.

Research output: Contribution to journalArticle

Hernandez, Ciria C. ; Zaika, Oleg ; Tolstykh, Gleb P. ; Shapiro, Mark S. / Regulation of neural KCNQ channels : Signalling pathways, structural motifs and functional implications. In: Journal of Physiology. 2008 ; Vol. 586, No. 7. pp. 1811-1821.
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