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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 59

plays an important role in regulating PLD activity (Module external signals can maintain information flowing through
2: Figure PLD signalling). the inositol 1,4,5-trisphosphate (InsP 3 )/Ca 2 + signalling
cassette.
PtdIns4,5P 2 regulation of ion channels and exchangers Operation of the PtdIns 3-kinase signalling cassette can
A number of ion channels and exchangers appear to be be considered in two parts:
regulated by PtdIns4,5P 2 . In some cases, the hydrolysis of
• Generation and metabolism of the 3-phosphorylated
PtdIns4,5P 2 results in channel opening as occurs for the
lipid messengers
transient receptor potential (TRP) vanilloid 1 (TRPV1)
• Mode of action of the 3-phosphorylated lipid messen-
channel, whereas the TRPC6 channel, TRP melastatin 4
gers
(TRPM4), TRP melastatin 7 (TRPM7) and TRP melast-
atin 8 (TRPM8) channels are closed (Module 2: Figure
One of the important functions of this pathway is to
PtdIns4,5P 2 regulation of TRP channels). In the case of regulate cell proliferation. Since a number of human can-
the inward rectifying K + channels, lipid hydrolysis res-
cers are found to have mutations in certain components
ults in channel opening (Module 2: Figure PtdIns4,5P 2 of this pathway, there is considerable interest in the re-
regulation of K + channels). Modulation of the TRPV1 lationship between PtdIns 3-kinase signalling and cancer.
channel is particularly important in hyperalgesia (Module A decline in the activity of this signalling pathway is the
10: Figure nociception). cause of insulin resistance that leads to diabetes (Module
Much of the information on this regulatory function
of PtdIns4,5P 2 has emerged from studies on K + chan- 12: Figure insulin resistance).
nels. Stimulation of phospholipase C (PLC) by G protein-
coupled receptors (GPCRs) causes a reduction in the level Generation and metabolism of the 3-phosphorylated
of PtdIns4,5P 2 , which results in a reduction in the activity lipid messengers
of some of the voltage-dependent K + (K v ) channels: Cells contain a number of phosphoinositides carrying a
phosphate on the 3-position (Module 2: Figure phosphoin-
• The human ether-a-go-go-related (HERG) K + channel ositide metabolism). One of these is PtdIns3,4,5P 3 ,which
(K v 11.1 channel) is the main second messenger operating in the PtdIns
• The K v 7.1 channel, which is coded for by the KCNQ1 3-kinase signalling pathway. This highly phosphorylated
gene, is regulated by PtdIns4,5P 2 . This inositol lipid lipid is generated in cells following activation of either
keeps the channel open, but when PtdIns4,5P 2 is hy- G protein-coupled or tyrosine kinase-coupled receptors
drolysed by angiotensin II, the channel closes. Such (Module 2: Figure PtdIns 3-kinase signalling).
lipid regulation is seen in adrenal zona glomerulosa cells These 3-phosphorylated lipid messengers are metabol-
(Module 7: Figure glomerulosa cell signalling)and also ized either by the type II inositol polyphosphate 5-phos-
in the heart. Mutation of KCNQ1 causes long QT) syn- phatases or by phosphatase and tensin homologue deleted
drome (LQT). on chromosome 10 (PTEN).
• The heteromultimer KCNQ2/3 is responsible for the
M channel in neurons and has been linked to a form of
Mode of action of the 3-phosphorylated lipid
epilepsy known as benign familial neonatal convulsions.
messengers
• KCNQ4, which codes for K v 7.4 (Module 3: Table
The lipid messengers PtdIns3,4P 2 and PtdIns3,4,5P 3 act
voltage-dependent K + channels), is the delayed rectifier
within the plane of the plasma membrane by binding to a
that controls K + efflux from sensory hair cells of the in- great variety of target proteins (Module 2: Figure PtdIns
ner ear. KCNQ4 mutations cause autosomal dominant 3-kinase signalling). Most of these downstream targets are
nonsyndromic deafness type 2 (DFNA2).
soluble proteins that translocate to the membrane by bind-
ing to the lipid messengers through various lipid-binding
PtdIns 3-kinase signalling domains [e.g. pleckstrin homology (PH), Phox homology
The PtdIns 3-kinase signalling cassette, which generates (PX), C2 domains and basic amino acid regions] (Module
the lipid second messenger phosphatidylinositol 3,4,5- 6: Figure modular lipid-binding domains). Once drawn on
tetrakis phosphate (PtdIns3,4,5P 3 ), has multiple functions to the membrane, these target proteins are activated and
in regulating a wide range of cellular processes such as the function as effectors to control a large number of cellular
control of glycogen metabolism, lipid synthesis, protein processes:
synthesis, gene transcription and cell growth, inflamma-
tion, cytoskeletal rearrangement and apoptosis (Module • Contribution to liver cell signalling mechanisms to con-
2: Figure PtdIns 3-kinase signalling). With regard to the trol glycogen metabolism (Module 7: Figure liver cell
latter, the PtdIns 3-kinase signalling cassette has a special signalling).
function in cell survival through its contribution to the • Functions in the insulin control of skeletal muscle gly-
hormonal modulation of apoptosis and by enhancing the cogen synthesis (Module 7: Figure skeletal muscle E-C
activity of the target of rapamycin (TOR). PtdIns 3-kinase coupling).
signalling is one of the major pathways used by the insulin • Functions in white fat cells to control lipid metabolism
receptor to regulate energy uptake and storage. (Module 7: Figure lipolysis and lipogenesis).
This lipid signalling pathway has a special relationship • Functions in the control of cell proliferation (Module 9:
to Ca 2 + signalling in that it can regulate the way in which Figure growth factor signalling).

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