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

Since many isoforms of adenylyl cyclase and adenosine 3', 5'-monophosphate (cAMP) phosphodiesterase have been cloned, it is likely that receptors of e ach hormone have a specific combination of these isoforms. Types I, III and VIII adenylyl cyclases are reported to be stimulated by Ca2+-calmodulin, t ype I phosphodiesterase by Ca2+-calmodulin, but types IV and VII (cAMP-spec ific) phosphodiesterases by Co2+. In the present study, we examined differe nt effects of Ca2+ and Co2+ On hormone-induced cAMP response in the isolate d perfused rat liver. The removal of Ca2+ from the perfusion medium (0 mM CaCl2 + 0.5 mM EGTA) di d not affect glucagon (0.1 nM)-responsive cAMP but reduced secretin (1 nM)- , vasoactive intestinal polypeptide (VIP, 1-10 nM)- and forskolin (1 muM)-r esponsive cAMP considerably. The addition of 1 mM CoCl2 reduced glucagon- a nd 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 CaCl2 + 0.5 mM EGTA + 3 mM CoCl2) than in the Ca2+-free perfusion alone . These results suggest that secretin, VIP1 and VIP2 receptors are linked to Ca2+-calmodulin-sensitive adenylyl cyclase; glucagon receptor to Ca2+-calmo dulin-insensitive adenylyl cyclase; VIP1 receptor to Ca2+-calmodulin-depend ent phosphodiesterase; glucagon, secretin and VIP2 receptors to cAMP-specif ic phosphodiesterase, respectively, in the rat liver. (C) 2001 Elsevier Sci ence B.V. All rights reserved.