Dynamic Metabolic Control of an Ion Channel

Prog Mol Biol Transl Sci. 2014;123:219-47. doi: 10.1016/B978-0-12-397897-4.00008-5.

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.

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.

Publication types

  • Review

MeSH terms

  • Animals
  • GTP-Binding Proteins / metabolism
  • Humans
  • Ion Channel Gating*
  • Ion Channels / metabolism*
  • Models, Biological
  • Receptors, G-Protein-Coupled / metabolism
  • Type C Phospholipases / metabolism

Substances

  • Ion Channels
  • Receptors, G-Protein-Coupled
  • Type C Phospholipases
  • GTP-Binding Proteins