Page 49 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 49

Module 2: Figure inositol phosphate metabolism

[PP] InsP (InsP )
8
ATP 2 4
16 15

PPInsP (InsP )
ADP + Pi 5 7
14 15
ATP InsP
6 PP-InsP 4
17
14
13 12

Ins1,3,4,5,6P
5
17 8 10 11 12
9
g
n Ins1,3,4,5P Ins1,3,4,6P 4 Ins3,4,5,6P Ins1,4,5,6P
i 4 4 4 4
l
l
a +
n 1 7
g 4
i -
s
Ins1,4,5P
d 3 Ins1,3,4P 3
i
p 2
i
l 17

l 1 5
o
t
i
s
o Ins1,4P 2 Ins4,5P 2 Ins1,3P 2 Ins3,4P 2
n -
I Cl
2 6 5
Ins4P Ins1P Ins3P
3 3 3
Inositol lipid
Inositol
synthesis
Inositol phosphate metabolism.
The major input into this metabolic system is the Ins1,4,5P 3 released from the membrane following receptor-activated inositol lipid signalling. One of
the functions of this pathway is to form free inositol that is used for inositol lipid synthesis. The pathway also generates additional inositol phosphates
(highlighted in pink) that have putative signalling functions. See the text for further details of the enzymes responsible for Steps 1--17.

diacylglycerol (DAG) (Module 2: Figure InsP 3 and DAG • Inositol 1,4,5-trisphosphate (InsP 3 )and Ca 2 + release
formation). This is a bifurcating signalling pathway in that
InsP 3 generates a Ca 2 + signal, whereas DAG functions to
stimulate protein kinase C (PKC). The InsP 3 released from PtdIns conversion into the precursor lipid PtdIns4,5P 2
the membrane diffuses into the cytosol where it engages The precursor PtdIns4,5P 2 , which is hydrolysed to give
the InsP 3 receptors (InsP 3 Rs) to release Ca 2 + from the InsP 3 , is part of the complex inositol lipid metabolic path-
endoplasmic reticulum. way (Module 2: Figure phosphoinositide metabolism). The
The operation of this InsP 3 /Ca 2 + signalling cassette can synthesis of the lipid precursor PtdIns4,5P 2 from PtdIns is
be divided into separate components: controlled by two substrate cycles involving lipid kinases
and phosphatases (Module 2: Figure InsP 3 and DAG form-
• PtdIns conversion into the precursor lipid PtdIns4,5P 2 ation). In the first step, the hydroxy group at the 4-position
• Hydrolysis of PtdIns4,5P 2 to generate InsP 3 and DAG of the inositol ring is phosphorylated to form PtdIns4P.
• Metabolism of InsP 3 and DAG and the resynthesis of In the next step, the PtdIns4P is phosphorylated further
PtdIns to yield the precursor PtdIns4,5P 2 . The next step is the

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