Simulations demonstrate the effects of receptor levels on [cAMP] in the absence and presence of PDE4 activity. Solid circles represent normalized peak cAMP levels (from model simulations) in response to a 5-min stimulation with isoproterenol. Open circles represent cAMP levels measured at the end of the second stimulation with isoproterenol (following a 5-min stimulation with 1 μM isoproterenol followed by a 5-min wash). (A–F) The effects of receptor desensitization in the following scenarios: (A) high receptor levels (100 μM) and PDE4 activity inhibited (10 μM rolipram); (B) low receptor levels (1 μM) and PDE activity inhibited; (C) high receptor levels with basal PDE activity (20 nM PKI to inhibit PKA activity); (D) low receptor levels with basal PDE activity; (E) high receptor levels and PKA-mediated regulation of PDE activity intact; (F) low receptor levels and PKA-mediated regulation of PDE activity intact.