Cyclic nucleotide compartmentalization: contributions of phosphodiesterases and ATP-binding cassette transporters.
Cyclic nucleotides [e.g., cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)] are ubiquitous second messengers that affect multiple cell functions from maturation of the egg to cell division, growth, differentiation, and death. The concentration of cAMP can be regulated by processes within membrane domains (local regulation) as well as throughout a cell (global regulation). The phosphodiesterases (PDEs) that degrade cAMP have well-known roles in both these processes. It has recently been discovered that ATP-binding cassette (ABC) transporters contribute to both local and global regulation of cAMP. This regulation may require the formation of macromolecular complexes. Some of these transporters are ubiquitously expressed, whereas others are more tissue restricted. Because some PDE inhibitors are also ABC transporter inhibitors, it is conceivable that the therapeutic benefits of their use result from the combined inhibition of both PDEs and ABC transporters. Deciphering the individual contributions of PDEs and ABC transporters to such drug effects may lead to improved therapeutic benefits.
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Satish
S
Cheepala
Jean-Sebastien
JS
Hulot
Jessica A
JA
Morgan
Yassine
Y
Sassi
Weiqiang
W
Zhang
Anjaparavanda P
AP
Naren
John D
JD
Schuetz
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D006801:Humans; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*
D018528:ATP-Binding Cassette Transporters; D009712:Nucleotides, Cyclic; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP