TY - CHAP
T1 - Dynamic metabolic control of an ion channel
AU - Hille, Bertil
AU - Dickson, Eamonn J
AU - Kruse, Martin
AU - Falkenburger, Bjoern
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Calcium
KW - FRET
KW - G-protein-coupled receptor
KW - Inositol 1,4,5-trisphosphate
KW - K channel
KW - M current
KW - Patch clamp
KW - Phosphatidylinositol 4,5-bisphosphate
KW - Phospholipase C
KW - Virtual Cell
UR - http://www.scopus.com/inward/record.url?scp=84896738266&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84896738266&partnerID=8YFLogxK
U2 - 10.1016/B978-0-12-397897-400008-5
DO - 10.1016/B978-0-12-397897-400008-5
M3 - Chapter
C2 - 24560147
AN - SCOPUS:84896738266
SN - 9780123978974
VL - 123
T3 - Progress in Molecular Biology and Translational Science
SP - 219
EP - 247
BT - Computational Neuroscience
PB - Elsevier
ER -