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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 60

Module 2: Figure PtdIns4,5P 2 regulation of K + channels

AGONIST
Channel open + Channel closed
membrane K membrane
hyperpolarized depolarized

R
PtdIns PtdIns4P PLC
4-Kinase 5-Kinase PtdIns4,5P
PtdIns PtdIns4P 2
InsP
3
DAG

DAG
Inositol Kinase
phosphate
metabolism
PtdIns
Inositol
Phosphatidic
PtdIns acid
synthase

Regulation of K + channels by agonist-dependent hydrolysis of PtdIns4,5P 2 .
A number of different K + channels are activated when they bind to PtdIns4,5P 2 . Upon stimulation by agonists that are coupled to phospholipase
C (PLC), this lipid is hydrolysed to InsP 3 and diacylglycerol (DAG), and this removal causes the channel to shut. The channel will open again when
another PtdIns4,5P 2 molecule associates with the lipid-binding site. The supply of PtdIns4,5P 2 is maintained by the resynthesis of PtdIns and its
rephosphorylation by PtdIns 4-kinase and then by PtdIns4P 5-kinase (Module 2: Figure InsP 3 /DAG recycling).

Module 2: Figure PtdIns4,5P 2 regulation of TRP channels

AGONIST Cations
TRPC6
TRPM4 TRPM4
TRPM7 TRPM7
TRPM8 TRPV1 TRPM8
closes
TRPV1 opens

R
PLC
PtdIns PtdIns4P
4-Kinase
PtdIns PtdIns4P 5-Kinase PtdIns4,5P 2
InsP
3

DAG
Inositol
phosphate
metabolism DAG
Kinase
PtdIns
Inositol
PtdIns Phosphatidic
synthase acid

Regulation of TRP channels by agonist-dependent hydrolysis of PtdIns4,5P 2 .
A number of transient receptor potential (TRP) channels are opened (TRPM4, TRPM7 and TRPM8) or closed (TRPV1) when they are bound to
PtdIns4,5P 2 . Upon stimulation by agonists that are coupled to phospholipase C (PLC), this lipid is hydrolysed, and its removal causes the channel to
open (TRPV1) or closed (TRPM4, TRPM7 and TRPM8). The channel returns to the resting state when PtdIns4,5P 2 re-associates with the lipid-binding
site. The supply of PtdIns4,5P 2 is maintained by the resynthesis of PtdIns and its sequential phosphorylation by PtdIns 4-kinase and PtdIns4P 5-kinase.
The operation of this signalling system is particularly important in nociception (Module 10: Figure nociception).

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