title: Dynamic metabolic control of an ion channel.
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.
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, Washington, USA.
authors.forename: Bertil
authors.initials: B
authors.lastname: Hille
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, Washington, USA.
authors.forename: Eamonn
authors.initials: E
authors.lastname: Dickson
authors.affiliation: Department of Physiology and Biophysics, University of Washington, Seattle, Washington, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Kruse
authors.affiliation: Department of Neurology, RWTH Aachen University, Aachen, Germany.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Falkenburger
mesh_terms: D000818:Animals; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism*; D008954:Models, Biological; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D007473:Ion Channels; D043562:Receptors, G-Protein-Coupled; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins
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