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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 39

NAADP and cell regulation the actin cytoskeleton, membrane trafficking, exocytosis,
The amount of Ca 2 + released by NAADP is relatively ion channels and exchangers.
small and is unlikely to have a direct role in Ca 2 + sig- Alterations in the activity of this phosphoinositide
nalling. However, there are suggestions that it may act lipid signalling pathway have been implicated in various
indirectly to trigger the release of Ca 2 + by the other re- diseases such as manic-depressive illness, Lowe’s oculo-
lease channels [ryanodine receptors (RYRs) or the inositol cerebrorenal (OCRL) syndrome and Cowden’s disease.
1,4,5-trisphosphate receptors (InsP 3 Rs) (Module 2: Figure
cADPR/NAADP function)]. Phosphoinositide metabolism
NAADP has been implicated in the control of insulin re- Phosphoinositide metabolism can be separated into two
lease by β-cells (Module 7: Figure β-cell signalling)and in main components (Module 2: Figure phosphoinositide
the control of secretion by pancreatic acinar cells (Module metabolism):
7: Figure control of pancreatic secretion).
• Inositol lipid metabolism concerns the pathways re-
sponsible for converting PtdIns into a variety of
ADP-ribosyl cyclase phosphoinositide lipid signalling molecules.
ADP-ribosyl cyclase is the enzyme responsible for syn- • Inositol phosphate metabolism is responsible for creat-
thesizing the Ca 2 + mobilizing messengers cADPR and ing a large array of inositol phosphates, some of which
NAADP. During cADPR generation and metabolism it function in the multipurpose inositol polyphosphate
uses NAD + to make cADPR through a cyclization reac- signalling pathway. This metabolic pathway also forms
tion (Module 2: Figure cADPR/NAADP function). The the inositol that is used to resynthesize the lipid pre-
same enzyme is also responsible for the hydrolysis of cursor PtdIns.
cADPR to ADPR. This enzyme can also use NADP as a
substrate to produce NAADP through a base-exchange re- These two pathways are connected by the processes of
action during which the nicotinamide group is exchanged lipid hydrolysis and lipid synthesis. The hydrolysis occurs
for nicotinic acid. when external signals activate phospholipase C (PLC) to
In mammals, this bifunctional enzyme appears to be the hydrolyse PtdIns4,5P 2 to form the second messengers in-
lymphocyte antigen CD38, which is expressed widely and ositol 1,4,5-trisphosphate (Ins1,4,5P 3 ) and diacylglycerol
is located both in the plasma membrane and at internal (DAG). The Ins1,4,5P 3 is one of the major inputs into the
sites. inositol phosphate metabolic pathway that produces the
inositol required for lipid synthesis.
This complex phosphoinositide metabolic network par-
ticipates in a number of highly versatile signalling cas-
Phosphoinositide signalling settes (Module 2: Figure phosphoinositide signalling sys-
Signalling through the phosphoinositide lipids is com- tems):
plex because there are a number of signalling cassettes
associated with both the synthesis and hydrolysis of the • Inositol 1,4,5-trisphosphate (InsP 3 )/Ca 2 + signalling
phosphoinositides. Phosphoinositide metabolism can be cassette
divided into two main parts. Firstly, there is inositol lipid • Diacylglycerol (DAG)/protein kinase C (PKC) sig-
metabolism, which describes the way in which the parent nalling cassette
molecule PtdIns is metabolized to form a number of lipid • PtdIns 3-kinase signalling
intermediates, some of which are key elements in differ- • PtdIns4,5P 2 signalling cassette
ent signalling cassettes. Secondly, there is inositol phos- • Multipurpose inositol polyphosphate signalling path-
phate metabolism, which is a complex pathway respons- way
ible for metabolizing soluble inositol phosphates. Some
of the inositol phosphates generated by this metabolism Inositol lipid metabolism
have been implicated as messengers operating within the The different phosphoinositide signalling pathways are
multipurpose inositol polyphosphate signalling pathway. derived from the parent molecule phosphatidylinositol
PtdIns4,5P 2 is of particular interest because it is (PtdIns) (Module 2: Figure PtdIns structure). Unlike the
the precursor used to generate the second messen- other phospholipids found in cellular membranes, PtdIns
gers inositol 1,4,5-triphosphate (InsP 3 ) and diacylglycerol is unique in that the free hydroxy groups at the 3-, 4- and
(DAG) that function in the inositol 1,4,5-trisphosphate 5-positions on the inositol ring can be phosphorylated
(InsP 3 )/Ca 2 + signalling cassette and the diacylglycerol further to create a family of phosphoinositides (Module
(DAG)/protein kinase C (PKC) signalling cassette respect- 2: Figure phosphoinositide metabolism). One of the more
ively. PtdIns4,5P 2 is also a precursor that is metabolized to important lipids involved in phosphoinositide signalling is
PtdIns3,4P 2 and PtdIns3,4,5P 3 , which function as second PtdIns4,5P 2 , which is a nodal point for a number of sig-
messengers to activate protein kinases in the PtdIns 3-k- nalling systems (Module 2: Figure phosphoinositide sig-
inase signalling pathway. In addition to being a precursor nalling systems).
for these various signalling pathways, PtdIns4,5P 2 can also The metabolism of PtdIns is carried out by a collection
function as a messenger for the PtdIns4,5P 2 signalling cas- of inositol lipid kinases and inositol lipid phosphatases.
sette, where localized synthesis or hydrolysis of this lipid The numbers below refer to the different reactions shown
functions to regulate a number of cellular systems such as in Module 2: Figure phosphoinositide metabolism:

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