Dynamic metabolic control of an ion channel

Bertil Hille, Eamonn J Dickson, Martin Kruse, Bjoern Falkenburger

Research output: Chapter in Book/Report/Conference proceedingChapter

11 Scopus citations

Abstract

G-protein-coupled receptors mediate responses to external stimuli in various cell types. We are interested in the modulation of KCNQ2/3 potassium channels by the Gq-coupled M1 muscarinic (acetylcholine) receptor (M1R). Here, we describe development of a mathematical model that incorporates all known steps along the M1R signaling cascade and accurately reproduces the macroscopic behavior we observe when KCNQ2/3 currents are inhibited following M1R activation. Gq protein-coupled receptors of the plasma membrane activate phospholipase C (PLC) which cleaves the minor plasma membrane lipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) into the second messengers diacylgycerol and inositol 1,4,5-trisphosphate, leading to calcium release, protein kinase C (PKC) activation, and PI(4,5)P2 depletion. Combining optical and electrical techniques with knowledge of relative abundance of each signaling component has allowed us to develop a kinetic model and determine that (i) M1R activation and M1R/Gβ interaction are fast; (ii) Gαq/Gβ separation and Gαq/PLC interaction have intermediate time constants; (iii) the amount of activated PLC limits the rate of KCNQ2/3 suppression; (iv) weak PLC activation can elicit robust calcium signals without net PI(4,5)P2 depletion or KCNQ2/3 channel inhibition; and (v) depletion of PI(4,5)P2, and not calcium/CaM or PKC-mediated phosphorylation, closes KCNQ2/3 potassium channels, thereby increasing neuronal excitability.

Original languageEnglish (US)
Title of host publicationComputational Neuroscience
PublisherElsevier
Pages219-247
Number of pages29
Volume123
ISBN (Print)9780123978974
DOIs
StatePublished - 2014
Externally publishedYes

Publication series

NameProgress in Molecular Biology and Translational Science
Volume123
ISSN (Print)18771173

Keywords

  • Calcium
  • FRET
  • G-protein-coupled receptor
  • Inositol 1,4,5-trisphosphate
  • K channel
  • M current
  • Patch clamp
  • Phosphatidylinositol 4,5-bisphosphate
  • Phospholipase C
  • Virtual Cell

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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  • Cite this

    Hille, B., Dickson, E. J., Kruse, M., & Falkenburger, B. (2014). Dynamic metabolic control of an ion channel. In Computational Neuroscience (Vol. 123, pp. 219-247). (Progress in Molecular Biology and Translational Science; Vol. 123). Elsevier. https://doi.org/10.1016/B978-0-12-397897-400008-5