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Am J Physiol Cell Physiol (October 31, 2001). doi:10.1152/ajpcell.00373.2001
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Articles in PresS, published online ahead of print October 31, 2001
Am J Physiol Cell Physiol, 10.1152/ajpcell.00373.2001
Submitted on August 3, 2001
Accepted on October 29, 2001

PKA-Dependent Activation of PDE3A and PDE4 and Inhibition of Adenylyl Cyclase V/VI in Smooth Muscle

Karnam S Murthy1*, Huiping Zhou1, and Gabriel M Makhlouf1

1 Physiology, Virginia Commonwealth University, Richmond, VA, USA

* To whom correspondence should be addressed. E-mail: skarnam{at}hsc.vcu.edu.

Regulation of adenylyl cyclase type V/VI and cAMP-specific, cGMP-inhibited PDE3 and cAMP-specific PDE4 by PKA and PKG was examined in gastric smooth muscle cells. Expression of PDE3A but not PDE3B was demonstrated by RT-PCR and Western blot. Basal PDE3 and PDE4 activities were present in a ratio of 2:1. Forskolin, isoproterenol, and the PKA activator, cBIMPS stimulated PDE3A phosphorylation and both PDE3A and PDE4 activities. Phosphorylation of PDE3A and activation of PDE3A and PDE4 were blocked by the PKA inhibitors, PKI and H-89, but not by the PKG inhibitor, KT5823. SNP inhibited PDE3 activity and augmented forskolin- and isoproterenol-stimulated cAMP levels; PDE3 inhibition was reversed by blockade of cGMP synthesis. Forskolin stimulated adenylyl cyclase phosphorylation and activity: PKI blocked phosphorylation and enhanced activity. Stimulation of cAMP and inhibition of IP3-induced Ca2+ release and muscle contraction by isoproterenol were augmented additively by PDE3 and PDE4 inhibitors. The results indicate that PKA regulates cAMP levels in smooth muscle via stimulatory phosphorylation of PDE3A and PDE4, and inhibitory phosphorylation of adenylyl cylcase type V/VI. Concurrent generation of cGMP inhibits PDE3 activity and augments cAMP levels.




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