PMID- 17956250
OWN - NLM
STAT- MEDLINE
DCOM- 20080205
LR  - 20211027
IS  - 0300-5127 (Print)
IS  - 0300-5127 (Linking)
VI  - 35
IP  - Pt 5
DP  - 2007 Nov
TI  - cAMP-specific phosphodiesterase-4D5 (PDE4D5) provides a paradigm for 
      understanding the unique non-redundant roles that PDE4 isoforms play in shaping 
      compartmentalized cAMP cell signalling.
PG  - 938-41
AB  - The PDE4 (phosphodiesterase-4) enzyme family consists of a distinct array of 
      N-terminal splice variant isoforms arising from four subfamily genes (4A, 4B, 4C 
      and 4D). These all hydrolyse specifically the intracellular second messenger 
      cAMP. Although identical in catalytic function, each isoform appears to serve a 
      non-superfluous regulatory role. For example, a beta-arrestin-sequestered 
      subpopulation of the PDE4D5 isoform specifically regulates the phosphorylation of 
      the beta(2)-AR (beta(2)-adrenergic receptor) by PKA (protein kinase A; also 
      called cAMP-dependent protein kinase). This was elucidated by the use of novel 
      technologies, including dominant-negative approaches, siRNA (small interfering 
      RNA) knockdown and spot-immobilized peptide array analyses. Functional phenotypes 
      uncovered using these methodologies have shown that beta-arrestin-sequestered 
      PDE4D5 shapes the spatial cAMP gradient around the membrane-bound beta(2)-AR, 
      regulating its phosphorylation by PKA and its ability to activate ERK 
      (extracellular-signal-regulated kinase) through G(i) in cardiomyocytes and 
      HEK-293 (human embryonic kidney)-B2 cells. This approach has provided the very 
      first identification of a non-redundant and specific role for a PDE isoform. The 
      fact that phenotypes can be uncovered by displacing PDE4 isoforms from specific 
      anchor sites using dominant-negative constructs and cell-permeable peptides 
      points to novel means for developing therapeutics aimed at disrupting 
      specifically sequestered PDE isoforms and even specifically sequestered 
      subpopulations of individual isoforms.
FAU - Lynch, M J
AU  - Lynch MJ
AD  - Division of Biochemistry and Molecular Biology, IBLS (Institute of Biomedical and 
      Life Sciences), Wolfson Building, University of Glasgow, Glasgow G12 8QQ, 
      Scotland, U.K.
FAU - Baillie, G S
AU  - Baillie GS
FAU - Houslay, M D
AU  - Houslay MD
LA  - eng
GR  - G0600765/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - England
TA  - Biochem Soc Trans
JT  - Biochemical Society transactions
JID - 7506897
RN  - 0 (Arrestins)
RN  - 0 (Receptors, Adrenergic, beta-2)
RN  - 0 (beta-Arrestins)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 3.1.4.- (Phosphoric Diester Hydrolases)
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  - Arrestins/chemistry/metabolism
MH  - Cell Compartmentation
MH  - Cell Line
MH  - Cyclic AMP/*metabolism
MH  - Cyclic Nucleotide Phosphodiesterases, Type 3
MH  - Cyclic Nucleotide Phosphodiesterases, Type 4
MH  - Humans
MH  - Phosphoric Diester Hydrolases/*metabolism
MH  - Phosphorylation
MH  - Receptors, Adrenergic, beta-2/metabolism
MH  - *Signal Transduction
MH  - beta-Arrestins
RF  - 41
EDAT- 2007/10/25 09:00
MHDA- 2008/02/06 09:00
CRDT- 2007/10/25 09:00
PHST- 2007/10/25 09:00 [pubmed]
PHST- 2008/02/06 09:00 [medline]
PHST- 2007/10/25 09:00 [entrez]
AID - BST0350938 [pii]
AID - 10.1042/BST0350938 [doi]
PST - ppublish
SO  - Biochem Soc Trans. 2007 Nov;35(Pt 5):938-41. doi: 10.1042/BST0350938.