Role of cyclic nucleotides in the control of hepatic autophagy

Using isolated hepatocytes as a model system we have investigated whether the cyclic nucleotides cAMP and cGMP are involved in the regulation of the autophagic process. The dibutyryl-cyclic nucleotide analogues db-cAMP and db-cGMP both inhibited autophagic sequestration, suggesting that cAMP and cGMP may be of significance for this step. The adenylate cyclase stimulator deacetyl-forskolin both raised the level of intracellular cAMP and reduced sequestration markedly. In contrast, the guanylate cyclase stimulating agent atriopeptin did not affect sequestration although, it effectively elevated, the level of cGMP. Several inhibitors of cyclic nucleotide phosphodiesterases strongly suppressed autophagy and elevated the level of both cAMP and cGMP. However, one inhibitor, milrinone, raised the cAMP level 3-4 x while having no significant effect on cGMP. These results suggest that cAMP may be involved in the control of hepatic autophagy, whereas the role of cGMP, if any, remains unclear.