Hormone-specific combinations of isoforms of adenylyl cyclase and phosphodiesterase in the rat liver

Abstract Since many isoforms of adenylyl cyclase and adenosine 3′, 5′-monophosphate (cAMP) phosphodiesterase have been cloned, it is likely that receptors of each hormone have a specific combination of these isoforms. Types I, III and VIII adenylyl cyclases are reported to be stimulated by Ca 2+ -calmodulin, type I phosphodiesterase by Ca 2+ -calmodulin, but types IV and VII (cAMP-specific) phosphodiesterases by Co 2+ . In the present study, we examined different effects of Ca 2+ and Co 2+ on hormone-induced cAMP response in the isolated perfused rat liver. The removal of Ca 2+ from the perfusion medium (0 mM CaCl 2 +0.5 mM EGTA) did not affect glucagon (0.1 nM)-responsive cAMP but reduced secretin (1 nM)-, vasoactive intestinal polypeptide (VIP, 1–10 nM)- and forskolin (1 μM)-responsive cAMP considerably. The addition of 1 mM CoCl 2 reduced glucagon- and secretin-responsive cAMP considerably, forskolin-responsive cAMP partly, did not affect 1 nM VIP-responsive cAMP, but enhanced 10 nM VIP-responsive cAMP. Forskolin- and VIP-responsive cAMP was greater in the combination (0 mM CaCl 2 +0.5 mM EGTA+3 mM CoCl 2 ) than in the Ca 2+ -free perfusion alone. These results suggest that secretin, VIP 1 and VIP 2 receptors are linked to Ca 2+ -calmodulin-sensitive adenylyl cyclase; glucagon receptor to Ca 2+ -calmodulin-insensitive adenylyl cyclase; VIP 1 receptor to Ca 2+ -calmodulin-dependent phosphodiesterase; glucagon, secretin and VIP 2 receptors to cAMP-specific phosphodiesterase, respectively, in the rat liver.