high affinity cGMP-specific 3',5'-cyclic phosphodiesterase 9A (PDE9A)
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Function
guanosine 3',5'-cyclic phosphate + H2O = guanosine 5'-phosphate
- 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:
- inhibited by zaprinast
Structure
- composed of a C-terminal catalytic domain containing two putative divalent metal sites & an N-terminal regulatory domain
- belongs to the cyclic nucleotide phosphodiesterase family, PDE9 subfamily
Compartment
- isoform PDE9A1:
- cell projection, ruffle membrane. cytoplasm, perinuclear region, Golgi, endoplasmic reticulum
- isoform PDE9A2:
- cell projection, ruffle membrane. cytoplasm, perinuclear region
- isoform PDE9A3: cytoplasm, endoplasmic reticulum
- isoform PDE9A17: cytoplasm, endoplasmic reticulum
Alternative splicing
named isoforms=16
Expression
- expressed in testis, brain, small intestine, skeletal muscle, heart, lung, thymus, spleen, placenta, kidney, liver, pancreas, ovary & prostate
- not expressed in blood
- highest expression in brain, heart, kidney, spleen, prostate & colon
- isoform PDE9A12 is found in prostate
Comparative biology
- inhibition of PDE9A prevents, & even reverses, heart failure in mice with cardiac pressure overload[3]
- PDE9A inhibition in mice is not dependent on nitric oxide levels, which decline in cardiac hypertrophy & heart failure
More general terms
References
- ↑ UniProt http://www.uniprot.org/uniprot/O76083.html
- ↑ Entrez Gene http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=5152
- ↑ 3.0 3.1 Lee DI, Zhu G, Sasaki T et al. Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature 2015 Mar 26; 519:472 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25799991
Kuhn M. A big-hearted molecule. Nature 2015 Mar 26; 519:416 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25799985