G-protein-coupled receptor agonists augment adenylyl cyclase activity induced by forskolin in human corpus cavernosum smooth muscle cells

Recept Signal Transduct. 1997;7(2):121-32.


The goal of this study was to investigate the synergistic effects between G-protein-coupled receptor agonists and forskolin-induced activation of adenylyl cyclases, in cultured human corpus cavernosum smooth-muscle cells. Treatment of human corpus cavernosum smooth-muscle cells with forskolin (0.1-10 microM) produced an increase in cAMP synthesis in a concentration-dependent manner. Forskolin-induced adenylyl cyclase activity was markedly augmented by prostaglandin E1 (PGE1) and its metabolite, PGE0, isoproterenol, carbachol, and phenylephrine. Augmentation of forskolin-induced cAMP by PGE1, and PGE0 is probably mediated by prostaglandin E receptors (EP). Enhancement of forskolin-induced cAMP synthesis by isoproterenol is mediated by beta-adrenergic receptors (beta-AR), since this activity was inhibited by propranolol. Stimulation of forskolin-induced cAMP synthesis by carbachol is attributed to activation of muscarinic acetylcholine receptors (mAChR), as demonstrated by inhibition with atropine. The augmentation of forskolin-induced cAMP synthesis by phenylephrine, an alpha1-adrenergic receptor (AR) agonist, however, was unexpected and cannot be attributed to increased intracellular Ca2+, since treatment of cells with either the Ca2+ ionophore, A23187, or 80 mM KCl did not affect forskolin-induced cAMP synthesis. Stimulation of forskolin-induced cAMP synthesis by phenylephrine is explained by its binding to beta-AR and activation of Gs protein, since this augmentation was inhibited by the beta-AR antagonist, propranolol. This observation was further supported by physiological studies in organ bath chambers, in which forskolin-induced relaxation of precontracted corpus cavernosum strips was enhanced by phenylephrine. These studies suggest that synergism between agonist-induced cAMP synthesis and forskolin is attributed to increased conformational stabilization of activated adenylyl cyclase catalytic domains by forskolin and the Gs(alpha)-subunit of activated Gs proteins.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenylyl Cyclases / drug effects*
  • Alprostadil / analogs & derivatives
  • Alprostadil / pharmacology
  • Carbachol / pharmacology
  • Cells, Cultured
  • Colforsin / pharmacology*
  • Drug Interactions
  • Enzyme Activation
  • GTP-Binding Proteins / metabolism*
  • Humans
  • Isoproterenol / pharmacology
  • Male
  • Models, Biological
  • Muscle Relaxation / drug effects
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / physiology*
  • Penis / cytology
  • Penis / physiology*
  • Phenylephrine / pharmacology
  • Receptors, Adrenergic, beta / metabolism
  • Receptors, Cell Surface / agonists*
  • Receptors, Cholinergic / metabolism
  • Signal Transduction


  • Receptors, Adrenergic, beta
  • Receptors, Cell Surface
  • Receptors, Cholinergic
  • Colforsin
  • Phenylephrine
  • Carbachol
  • prostaglandin E0
  • GTP-Binding Proteins
  • Adenylyl Cyclases
  • Alprostadil
  • Isoproterenol