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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 66

Module 2: Figure NO and cyclic GMP signalling

Atrial natriuretic factor (ANP), C-type natriuretic factor (CNP)
Brain natriuretic factor (BNP), Guanylin
2+
Ca
NO
pGC CNGC s
e
s
n
o
2+ eNOS Protein p
Ca iNOS cGK I s e
nNOS GCK GC cGK II targets r
sGC r a
l
u
l
l
NO GC cGMP PDE5 GMP e C
- 2+
O 2 GSH Mn NADPH
RNS NADP +
signalling TRXR
- 2+ SH SH S S HNO
ONO O GS-NO Mn - NO
TRX TRX
Cy-SH S-Nitrosylation Cy-SNO Denitrosylation Cy-SH
GSH GSNO
Protein NADH
target Cellular responses GSNOR GSNHOH
NAD +

Nitric oxide (NO) and cyclic GMP (cGMP) signalling pathways.
The nitric oxide (NO) signal can either diffuse in from other cells as a paracrine signal or it can be generated within the cell by different NO synthases
(NOSs). The NO has two main actions. It can stimulate soluble guanylyl cyclase (sGC) to form the messenger cyclic GMP (cGMP), which can act
through cyclic nucleotide-gated channels (CNGCs) to promote Ca 2 + entry or it can activate cyclic GMP-dependent protein kinase (cGK). Cyclic GMP
is also formed by a plasma membrane guanylyl cyclase (pGC), which is part of the single membrane-spanning receptor activated by a variety of
peptides such as atrial natriuretic peptide (ANP), brain type natriuretic factor (BNP), C-type natriuretic factor (CNP) and guanylin. The other main action
is through reactive nitrogen species (RNS) signalling mechanisms that depend upon an S-nitrosylation reaction, which is reversed by denitrosylation
reactions.

the nucleus to form Ins1,4,5,6P 4 , functions as a transcrip- InsP 8 ([PP] 2 -InsP 4 )
tional regulator. InsP 8 is a diphosphoinositide that may function as a high-
Regulation of mRNA export from the nucleus energy store in that it can donate a high-energy phosphate
Studies on yeast indicate that InsP 6 formed by an inositol to ADP to form ATP.
polyphosphate kinase located on the nuclear pores may Nitric oxide (NO)/cyclic GMP signalling pathway
facilitate the export of mRNA from the nucleus.
Nitric oxide (NO) is a highly diffusible messenger, which
passes rapidly through cell membranes. It can act as
PP-InsP 4
This diphosphorylated inositol phosphate has been con- a second messenger within its cell of origin or it can
sidered as an orphan signal, as its function is unknown. Its diffuse across membranes to act on neighbouring cells as
level declines in response to either cyclic AMP or cyclic a paracrine signalling agent. NO synthesis is carried out
GMP. by nitric oxide synthase (NOS), which comes in three
different forms: neuronal nitric oxide synthase (nNOS),
InsP 7 (PP-InsP 5 ) inducible nitric oxide synthase (iNOS) and endothelial
This diphosphoinositide, which is formed by the phos- nitric oxide synthase (eNOS). These different isoforms
phorylation of InsP 6 by an InsP 6 kinase (see Step 14 in share a similar NO synthetic reaction mechanism,which
Module 2: Figure inositol phosphate metabolism), has been uses L-arginine as a substrate and O 2 and NADPH
implicated in a number of functions. It may serve as an en- as co-substrates to form NO. NOS regulation is very
ergy store as has been suggested for InsP 8 ([PP] 2 -InsP 4 ). different for the three isoforms and is partly dependent
InsP 7 has been shown to regulate insulin signalling by in- on the way they are located in different parts of the cell.
hibiting the activity of protein kinase B (PKB), which has The action of NO is complex in that it can transmit
a central role in the insulin receptor pathway responsible information in markedly different ways. One of its
for regulating a large number of insulin-sensitive processes actions is mediated through the cyclic GMP signalling
(Module 2: Figure insulin receptor). Through this inhib- pathway, where it stimulates soluble guanylyl cyclase to
itory effect on insulin signalling, InsP 7 may contribute to produce the cyclic GMP that can modify the properties
the onset of insulin resistance (Module 12: Figure insulin of ion channels, protein phosphatases or cyclic nucle-
resistance). otide phosphodiesterase. NO can also act through the

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