Page 50 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 50

Module 2: Figure InsP 3 and DAG formation
Agonist

Receptor Diacylglycerol
PtdIns PtdIns4P
PtdIns4,5P
2
Plasma
membrane

G q/11 PLC PKC
P P
PtdIns4P PtdIns4,5P 2 P OH
Pase Pase
P P P
Protein
PtdIns PtdIns4P phosphorylation
4-kinase 5-kinase P
InsP P P
3

Calcium signalling

Agonist-dependent formation of the second messengers inositol 1,4,5-trisphosphate (InsP 3 ) and diacylglycerol (DAG).
The inositol lipids that function in signalling are embedded in the inner leaflet of the plasma membrane. The precursor lipid is phosphatidylinositol
(PtdIns), which is successively phosphorylated, first on the 4-position to form PtdIns4P and then on the 5-position to form PtdIns4,5P 2 . Activated
cell-surface receptors are coupled through the G protein G q/11 to phospholipase C (PLC) that hydrolyses PtdIns4,5P 2 to generate inositol 1,4,5-
trisphosphate (InsP 3 ). InsP 3 activates Ca 2 + signalling, and diacylglycerol (DAG) stimulates protein kinase C (PKC) to initiate protein phosphorylation
(Module 2: Figure PKC structure and activation). An animated version of this figure is available.

agonist-dependent hydrolysis of PtdIns4,5P 2 to generate for diacylglycerol (DAG) metabolism. Similarly, there are
InsP 3 and diacylglycerol (DAG). two separate mechanisms of inositol 1,4,5-trisphosphate
(InsP 3 ) metabolism.
Hydrolysis of PtdIns4,5P 2 to generate InsP 3 and
diacylglycerol (DAG) Diacylglycerol (DAG) metabolism
External stimuli (e.g. hormones, neurotransmitters and The second messenger DAG is metabolized via two separ-
growth factors) gain access to this signalling pathway ate pathways. It can be phosphorylated by diacylglycerol
by activating cell-surface receptors. The latter fall into (DAG) kinase to form phosphatidic acid (PA) or it is hy-
two main classes, the G protein-coupled receptors (GP- drolysed by diacylglycerol (DAG) lipase.The PA is trans-
CRs) and the protein tyrosine kinase-linked receptors ferred to the endoplasmic reticulum, where it interacts
(PTKRs). During the transduction process, the precursor with CTP to form the CDP/DAG complex, which is a
lipid PtdIns4,5P 2 is hydrolysed by phospholipase C (PLC) precursor in the resynthesis of PtdIns (Module 2: Figure
to produce both InsP 3 and DAG. The family of PLCs InsP 3 /DAG recycling).
can be distinguished by the way they are coupled to cell-
surface receptors. In general, the GPCRs use the PLCβ Diacylglycerol (DAG) kinase
isoforms, whereas the receptor tyrosine kinases (RTKs) Diacylglycerol (DAG) kinase α (DAGKα), which is one
are coupled to the PLCγ isoforms (Module 2: Figure PLC of a family of nine mammalian isotypes, has a number
structure and function). of domains, including Ca 2 + -binding EF-hand motifs and
DAG functions to activate the diacylglycerol an N-terminal recoverin homology domain that is related
(DAG)/protein kinase C (PKC) signalling cassette, to the recoverin family of neuronal Ca 2 + sensors.These
whereas the InsP 3 diffuses into the cytosol to activate the two domains appear to function as a unit during Ca 2 + -
InsP 3 receptors to release Ca 2 + stored in the endoplasmic induced activation of DAGKα. In response to an increase
reticulum. The signalling function of this bifurcating sig- in Ca 2 + ,DAGKα translocates to the membrane, where it
nalling pathway is curtailed by the metabolism of InsP 3 phosphorylates DAG to phosphatidic acid (PA) (Module
and the resynthesis of PtdIns. 2: Figure InsP 3 /DAG recycling). DAG kinase functions
in the scission of COPI-coated vesicles that bud off from
Metabolism of InsP 3 and DAG and the resynthesis the Golgi (Module 4: Figure COPI-coated vesicles).
of PtdIns
The metabolism of InsP 3 and DAG and the resynthesis Diacylglycerol (DAG) lipase
of PtdIns are the OFF reactions that terminate the ac- A diacylglycerol (DAG) lipase is responsible for removing
tions of these two messengers. There are two pathways one of the fatty acid tails from the sn-position of DAG

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