cAMP-specific 3',5'-cyclic phosphodiesterase 4A; DPDE2; PDE46 (PDE4A, DPDE2)

Function

• hydrolyzes the second messenger cAMP
• purine metabolism; 3',5'-cyclic AMP degradation;
• AMP from 3',5'-cyclic AMP: step 1/1
• phosphorylated at Ser-686 & Ser-688 when expressed in S.frugiperda cells
• isoform 2 & isoform 7 are activated by phosphorylation at Ser-119 & Ser-123 respectively by PKA
• proteolytically cleaved by caspase-3
• isoform 1 interacts with LYN
• isoform 2 & isoform 6 interact weakly with LYN
• isoform 1, isoform 2 & isoform 6 interact with ARRB2

adenosine 3',5'-cyclic phosphate + H2O = adenosine 5'-phosphate

Kinetic parameters:

• KM=4.0 uM for cAMP (isoform 2)
• KM=3 uM for cAMP (isoform 6)

Cofactor:

• binds 2 divalent metal cations per subunit
• site 1 may preferentially bind Zn+2
• site 2 has a preference for Mg+2 &/or Mn+2

Inhibition:

• isoform 1, isoform 2, isoform 6 & isoform 7 are inhibited by rolipram & cilomilast
• isoform 1, isoform 2 & isoform 6 are inhibited by 4-[(3-butoxy-4-methoxyphenyl)-methyl]-2-imidazolidinone (Ro 20-1724), roflumilast & denbufylline

Structure

• belongs to the cyclic nucleotide phosphodiesterase family, PDE4 subfamily

Compartment

• isoform 1: cytoplasm, perinuclear region
• isoform 2: cytoplasm, perinuclear region, cell projection, ruffle membrane
• isoform 4: peripheral membrane
• isoform 6: cytoplasm, perinuclear region
• isoform 7: cytoplasm, membrane; predominantly cytoplasmic

Alternative splicing

• named isoforms=7
• additional isoforms seem to exist
• some isoforms may be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay probably represents a non-functional splice isoform

Expression

• isoform 1 is widely expressed
• isoform 2
  • abundant in liver, stomach, testis, thyroid gland & adrenal gland
  • also found in placenta, kidney, pancreas, ovary, uterus, skin, monocytes, mast cells, macrophages, muscle
• isoform 6
  • expressed at high levels in the heart & small intestine
  • also found in the brain, kidney, spleen, colon, salivary gland, ovary & peripheral blood lymphocytes
• isoform 7
  • expressed predominantly in skeletal muscle & brain
  • expressed at lower levels in the testis
  • found in specific neuronal subpopulations in the cerebral cortex, spinal cord & cerebellum (at protein level)

More general terms

• phosphodiesterase 4; cAMP specific phosphodiesterase (PDE4)

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=5141
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:5141
• OMIM: https://mirror.omim.org/entry/600126
• UniProt: http://www.uniprot.org/uniprot/P27815.html