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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 7

Module 2: Figure protein kinase A (PKA)

PKA I PKA II

RI RI RII RII
Tandem
C C cyclic AMP-binding C C
domains AKAP
Substrate Substrate

Cellular target
Cyclic AMP

RI RI
Cyclic AMP

RII RII

C C
P AKAP
C P P
Substrate Substrate Substrate Substrate
Cellular target

The functional organization of protein kinase A (PKA).
There are two types of PKA, type I PKA (PKA I) and type II PKA (PKA II), which differ primarily in the type of R subunits that associate with the C
subunits. There are four R subunit isoforms (RIα,RIβ,RIIα and RIIβ), which have somewhat different properties with regard to their affinity for cyclic
AMP and their ability to associate with the A-kinase-anchoring proteins (AKAPs). It is these different R subunits that define the properties of the two
types of PKA.

functions of EPACs is to activate Rap1 and Rap2B,which larmass32kDa (DARPP-32) co-ordinates the activ-
have many functions, many of which are related to con- ity of the dopamine and glutamate signalling pathways
trolling actin dynamics. In addition, the EPAC/Rap path- in medium spiny neurons (Module 10: Figure medium
way can activate phospholipase Cε (PLCε) and this mech- spiny neuron signalling).
anism has been implicated in the control of autophagy • Adrenaline-induced glycogenolysis in skeletal muscle
(Module 11: Figure autophagy signalling mechanisms). cells depends upon a cyclic AMP-dependent phos-
phorylation of phosphorylase kinase (Module 7: Figure
Cyclic AMP signalling functions skeletal muscle E-C coupling).
The cyclic AMP signalling pathway functions in the con- • Activation of the cyclic AMP-dependent transcription
trol of a wide range of cellular processes: factor cyclic AMP response element-binding protein
(CREB) contributes to the regulation of glucagon bio-
• Cyclic AMP suppresses spontaneous Ca 2 + oscillations
synthesis in glucagon-secreting α-cells (Module 7: Fig-
during oocyte maturation. ure α-cell signalling).
• Cyclic AMP has a potent anti-inflammatory action by
inhibiting the activity of macrophages (Module 11: Fig-
ure macrophage signalling) and mast cells (Module 11: Cyclic AMP hydrolysis
Figure mast cell inhibitory signalling). There are two OFF reactions of the cyclic AMP sig-
• Melanocortin 4 receptors (MC4Rs) on second-order nalling pathway, cyclic AMP efflux from the cell and cyclic
neurons use the cyclic AMP signalling pathway AMP hydrolysis. The latter is carried out by a family of
to induce the hypothalamic transcription factor phosphodiesterase enzymes that hydrolyse cyclic AMP to
Single-minded 1 (Sim1) to decrease food intake and AMP (Module 2: Figure cyclic AMP signalling).
weight loss (Module 7: Figure control of food intake).
• Cyclic AMP mediates the action of lipolytic hormones
in white fat cells by stimulating a hormone-sensitive Cyclic AMP efflux
lipase (Module 7: Figure lipolysis and lipogenesis). There are two OFF reactions for the cyclic AMP sig-
• Heat production by brown fat cells is controlled by nalling pathway, cyclic AMP hydrolysis and cyclic AMP
noradrenaline acting through cyclic AMP (Module 7: efflux from the cell (Module 2: Figure cyclic AMP sig-
Figure brown fat cell). nalling). The latter is carried out by ABCC4, which is one
• The phosphorylation of dopamine- and cyclic of the ATP-binding cassette (ABC) transporters (Module
AMP-regulated phosphoprotein of apparent molecu- 3: Table ABC transporters).

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