Page 5 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 5

Module 2: Table adenylyl cyclases
Regulatory properties and distribution of adenylyl cyclase.
Modulation by Ca 2 + , calmodulin
(CaM), Ca 2 + /CaM kinase II
Adenylyl cyclase (CaMKII), protein kinase C (PKC),
(AC) isoform Gα Gβγ Gα i or Gα o protein kinase A (PKA) Tissue distribution
AC1 ↑ ↓ ↓ Gα o ↑ CaM and PKC ↓ CaMKII Brain, adrenal medulla
AC2 ↑ ↑ -- ↑ PKC Brain, skeletal and cardiac muscle, lung
AC3 ↑ ↑ CaM and PKC ↓ CaMKII Brain, olfactory epithelium
AC4 ↑ ↑ ↑ PKC Brain, heart, kidney, liver
AC5 ↑ ↓ ↓ ↓ Ca 2 + and PKCα ↓ PKA Brain, heart, kidney, liver, lung, adrenal
AC6 ↑ ↓ ↓ ↑ PKC ↓ Ca 2 + and PKA Ubiquitous
AC7 ↑ ↑ ↑ PKC Ubiquitous, high in brain
AC8 ↑ ↑ CaM Brain, lung, heart, adrenal
AC9 ↑ Brain, skeletal muscle
AC10 -- -- -- Activated by HCO 3 − Testis
The membrane-bound adenylyl cyclases (AC1--AC9) are widely distributed. They are particularly rich in brain, but are also expressed in
many other cell types. The soluble AC10 is restricted to the testis. The primary regulation of the AC1--AC9 isoforms is exerted through
components of the heterotrimeric G proteins, which are dissociated upon activation of neurotransmitter and hormonal receptors into their
α and βγ subunits. They are all activated by Gα s , but only some of the isoforms are inhibited by Gα i . The Gβγ subunit is able to activate
some isoforms, but inhibits others. The isoforms also differ in the way they are modulated by components of other signalling pathways
such as Ca 2 + and PKC. Some of the others are inhibited by PKA, which thus sets up a negative-feedback loop whereby cyclic AMP can
inhibit its own production. Modified from Table I in Whorton and Sunahara 2003. Reproduced from Handbook of Cell Signaling, Volume 2
(edited by R.A. Bradshaw and E.A. Dennis), Whorton, M.R. and Sunahara, R.K., Adenylyl cyclases, pp. 419--426. Copyright (2003), with
permission from Elsevier.

by binding to the tandem cyclic AMP-binding domains to to free fatty acids and glycerol in both white fat cells
release active C subunits that then phosphorylate specific (Module 7: Figure lipolysis and lipogenesis)and in
substrates. Since the RI subunits have a higher cyclic AMP- brown fat cells (Module 7: Figure brown fat cell).
binding affinity, PKA I will be able to respond to the lower • PKA phosphorylates the phosphorylase kinase that
cyclic AMP concentrations found globally within the bulk converts inactive phosphorylase b into active phos-
cytoplasm. phorylase a in skeletal muscle (Module 7: Figure skeletal
muscle E-C coupling) and in liver cells (Module 7: Fig-
Protein kinase A (PKA) II ure glycogenolysis and gluconeogenesis).
A characteristic feature of Type II protein kinase A (PKA) • PKA activates the transcription factor cyclic AMP re-
is that the regulatory dimer is made up of RII sub- sponse element-binding protein (CREB) (Module 4:
units. Since this RII subunit has a much higher affin- Figure CREB activation). This activation is a critical
event in the induction of gluconeogenesis in liver cells
ity for the A-kinase-anchoring proteins (AKAPs), PKA
(Module 7: Figure liver cell signalling).
II is usually docked to this scaffolding protein and thus
• PKA inhibits the salt-inducible kinase 2 (SIK2) that nor-
has a much more precise localization to specific cellular
mally acts to phosphorylate TORC2, thereby prevent-
targets.
ing it from entering the nucleus to facilitate the activity
The substrates phosphorylated by cyclic AMP (Module
of CREB (Module 7: Figure liver cell signalling).
2: Figure cyclic AMP signalling) fall into two main groups:
the cyclic AMP substrates that regulate specific cellular • PKA phosphorylates inhibitor 1 (I1), which assists the
processes and the cyclic AMP substrates that are compon- protein phosphorylation process by inactivating protein
ents of other signalling systems. phosphatase 1 (PP1) .
Cyclic AMP substrates that regulate specific cellular • PKA contributes to the translocation and fusion of ves-
processes: icles with the apical membrane during the onset of acid
secretion by parietal cells (Module 7: Figure HCl secre-
• In neurons, cyclic AMP acts through PKA to phos- tion).
phorylate Ser-845 on the AMPA receptor (Module 3: • PKA phosphorylates the regulatory (R) domain on the
Figure AMPA receptor phosphorylation). cystic fibrosis transmembrane conductance regulator
• Cyclic AMP acting through PKA stimulates the (CFTR) to enable it to function as an anion channel
fructose-2,6-bisphosphatase component to lower the (Module 3: Figure CFTR channel).
level of fructose 2,6-bisphosphate, which reduces glyco- • In the small intestine, PKA phosphorylates the cystic
lysis and promotes gluconeogenesis (Module 2: Figure fibrosis transmembrane conductance regulator (CFTR)
AMPK control of metabolism). channel (Module 3: Figure CFTR channel)thatisre-
• In insulin-secreting β-cells, the salt-inducible kinase 2 sponsible for activating fluid secretion (Module 7: Fig-
(SIK2) that phosphorylates transducer of regulated cyc- ure intestinal secretion). Uncontrolled activation of
lic AMP response element-binding protein (TORC) cyclic AMP formation by cholera toxin results in
is inhibited by a cyclic AMP/PKA-dependent phos- cholera.
phorylation (Module 7: Figure β-cell signalling). • In kidney collecting ducts, cyclic AMP acts through
• PKA phosphorylates the hormone-sensitive lipase PKA to phosphorylate Ser-256 on the C-terminal cyto-
(HLS) that initiates the hydrolysis of triacylglycerol plasmic tail of aquaporin 2 (AQP2), enabling this water

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