PMID- 16246112
OWN - NLM
STAT- MEDLINE
DCOM- 20060223
LR  - 20221229
IS  - 0300-5127 (Print)
IS  - 0300-5127 (Linking)
VI  - 33
IP  - Pt 6
DP  - 2005 Dec
TI  - Beta-arrestin-recruited phosphodiesterase-4 desensitizes the AKAP79/PKA-mediated 
      switching of beta2-adrenoceptor signalling to activation of ERK.
PG  - 1333-6
AB  - Using combined dominant-negative and siRNA (small interfering RNA)-mediated 
      knockdown strategies, the functional importance of specific PDE4 
      (phosphodiesterase-4) isoforms in modifying signalling through the beta2-AR 
      (beta2-adrenoceptor) has been uncovered. The PDE4D5 isoform preferentially 
      interacts with the signalling scaffold protein beta-arrestin and is thereby 
      recruited to the beta2-AR upon agonist challenge. Delivery of an active PDE to 
      the site of cAMP synthesis at the plasma membrane specifically attenuates the 
      activity of a pool of PKA (protein kinase A) that is tethered to the beta2-AR via 
      AKAP79 (A-kinase anchoring protein 79). The specific functional role of this 
      anchored PKA is to phosphorylate the beta2-AR and allow it to switch its coupling 
      with G(i) and thereby activation of ERK (extracellular-signal-regulated kinase). 
      Our studies uncover a novel facet of the regulation of beta2-AR signalling by 
      showing that beta-arrestin-recruited PDE4 provides the means of desensitizing the 
      agonist-dependent coupling of beta2-AR with G(i) and its consequential activation 
      of ERK.
FAU - Houslay, M D
AU  - Houslay MD
AD  - Division of Biochemistry and Molecular Biology, IBLS, Wolfson Building, 
      University of Glasgow, Glasgow G12 8QQ, Scotland, UK. M.Houslay@bio.gla.ac.uk
FAU - Baillie, G S
AU  - Baillie GS
LA  - eng
GR  - G8604010/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem Soc Trans
JT  - Biochemical Society transactions
JID - 7506897
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Arrestins)
RN  - 0 (Isoenzymes)
RN  - 0 (Receptors, Adrenergic, beta-2)
RN  - 0 (beta-Arrestins)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases)
RN  - EC 3.1.4.- (Phosphoric Diester Hydrolases)
RN  - EC 3.1.4.17 (3',5'-Cyclic-AMP Phosphodiesterases)
RN  - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
RN  - EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)
RN  - EC 3.1.4.17 (PDE4D protein, human)
SB  - IM
MH  - 3',5'-Cyclic-AMP Phosphodiesterases/*metabolism
MH  - Adaptor Proteins, Signal Transducing/*metabolism
MH  - Animals
MH  - Arrestins/*metabolism
MH  - Cyclic AMP/metabolism
MH  - Cyclic AMP-Dependent Protein Kinases/*metabolism
MH  - Cyclic Nucleotide Phosphodiesterases, Type 3
MH  - Cyclic Nucleotide Phosphodiesterases, Type 4
MH  - Enzyme Activation
MH  - Extracellular Signal-Regulated MAP Kinases/*metabolism
MH  - Humans
MH  - Isoenzymes/metabolism
MH  - Phosphoric Diester Hydrolases/metabolism
MH  - Receptors, Adrenergic, beta-2/*metabolism
MH  - Signal Transduction/*physiology
MH  - beta-Arrestins
EDAT- 2005/10/26 09:00
MHDA- 2006/02/24 09:00
CRDT- 2005/10/26 09:00
PHST- 2005/10/26 09:00 [pubmed]
PHST- 2006/02/24 09:00 [medline]
PHST- 2005/10/26 09:00 [entrez]
AID - BST20051333 [pii]
AID - 10.1042/BST0331333 [doi]
PST - ppublish
SO  - Biochem Soc Trans. 2005 Dec;33(Pt 6):1333-6. doi: 10.1042/BST0331333.