Page 6 - 85 cell signalling pathways

Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 6

Module 2: Figure cyclic AMP signalling

Stimulatory agonists Inhibitory agonists
Adenylyl
cyclase
GDP
S i
GDP
Cholera
toxin
- S + - i ABCC4
GTP GTP
HCO + Cyclic
3
Soluble adenylyl cyclase AMP PDE
5’AMP
+ +
EPAC
CNGC
PLC Rap1 PKA + Ca 2+
+ P
DAG InsP 3 +
+ CFTR
+ + P
Cyclic + +
GMP + + AMPAR
P 2+
P Ca P
cGMP PDE
P P RYR
CREB P P
5’GMP P Ca 1.1
V
P
F-2,6-P 2 PLN Ca 1.2
phosphatase Lipase Phosphorylase V
kinase SERCA ER/SR
Organization and function of the cyclic AMP signalling pathway.
Cyclic AMP is formed both by membrane-bound adenylyl cyclase and by the bicarbonate-sensitive soluble adenylyl cyclase. The former is regulated
by both stimulatory agonists that act through the α S subunit or through inhibitory agonists that act through either the α i or the βγ subunits. The
increase in cyclic AMP then acts through three different effector systems. It acts through the exchange protein activated by cyclic AMP (EPAC), which
functions to activate Rap1. It can open cyclic nucleotide-gated channels (CNGCs). The main action of cyclic AMP is to activate protein kinase A (PKA)
to phosphorylate a large number of downstream targets. Some of these drive specific processes such as gene transcription through phosphorylation
of cyclic AMP response element-binding protein (CREB), and activation of ion channels [e.g. AMPA receptors and cystic fibrosis transmembrane
conductance regulator (CFTR)] and various enzymes that control metabolism [e.g. fructose 2,6-bisphosphate (F-2,6-P 2 ) 2-phosphatase, lipase and
phosphorylase kinase]. Other downstream targets are components of other signalling pathways such as the cyclic GMP phosphodiesterase (cGMP
PDE), the phospholamban (PLN) that controls the sarco/endo-plasmic reticulum Ca 2 + -ATPase (SERCA), the ryanodine receptor (RYR) and the Ca 2 +
channels Ca V 1.1 and Ca V 1.2.
channel to fuse with the apical membrane to allow wa- • The ryanodine receptor 2 (RYR2) is modulated by phos-
ter to enter the cell (Module 7: Figure collecting duct phorylation through PKA, which is associated with the
function). cytoplasmic head through an AKAP (Module 3: Figure
• In blood platelets, cyclic AMP activates the ryanodine receptor structure).
phosphorylation of vasodilator-stimulated phos- • Sarco/endo-plasmic reticulum Ca 2 + -ATPase 2a
phoprotein (VASP), which is a member of the (SERCA2a) increases its Ca 2 + -pumping activity when
Ena/vasodilator-stimulated phosphoprotein (VASP) the inhibitory effect of phospholamban (PLN) is
family resulting in a decrease in the actin-dependent removed following its phosphorylation by PKA on
processes associated with clotting (Module 11: Figure Ser-16 (Module 5: Figure phospholamban mode of
platelet activation). action).
Cyclic AMP substrates that are components of other Salt-inducible kinase 2 (SIK2)
signalling systems:
The salt-inducible kinase 2 (SIK2) functions to phos-
• Phosphorylation of the cyclic GMP phosphodiesterase phorylate the transducer of regulated CREB (TORC2),
PDE1A by PKA results in a decrease in its sensitivity thereby preventing it from entering the nucleus to facil-
to Ca 2 + activation. itate the activity of the transcriptional factor cyclic AMP
• Entry of Ca 2 + through the L-type Ca V 1.1 channel response element-binding protein (CREB) (Module 4: Fig-
(Module 3: Figure Ca V 1.1 L-type channel)and theL- ure CREB activation). It functions to regulate TORC2
type Ca V 1.2 channel (Module 3: Figure Ca V 1.2 L-type in liver cells (Module 7: Figure liver cell signalling)and
channel) is enhanced through PKA-dependent phos- in insulin-secreting β-cells (Module 7: Figure β-cell sig-
phorylation. nalling).
• PKA-dependent phosphorylation of dopamine- and
cyclic AMP-regulated phosphoprotein of apparent mo- Exchange proteins activated by cyclic
lecular mass 32 kDa (DARPP-32) functions as a molecu- AMP (EPACs)
lar switch to regulate the activity of protein phosphatase Other targets for the second messenger cyclic AMP are the
1 (PP1). exchange proteins activated by cAMP (EPACs). One of the

C 2012 Portland Press Limited www.cellsignallingbiology.org