Regulation of hepatic nuclear guanylate cyclase.

Abstract

In immunohistochemical studies of rat liver tissue slices and purified nuclei, c[cyclic]AMP and cGMP immunofluorescence on the nuclear membrane are sequentially increased after glucagon administration. An explanation for the increased cGMP immunofluorescence was sought in experiments in which guanylate cyclase [GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2] activity of hepatic subcellular fractions was determined. A nuclear guanylate cyclase exists which can be distinguished from the soluble and crude particulate guanylate cyclases. The activity of the nuclear enzyme was increased by 35% in nuclei isolated from rats 30 min after glucagon injection, the time at which maximal nuclear membrane cGMP immunofluorescence is observed. Because glucagon altered both cAMP location and levels prior to the observed changes in nuclear cGMP metabolism, the hypothesis that cAMP acted as the 2nd messenger was tested. In vitro incubation of nuclei isolated from control rats with 10-5 M cAMP produced a 25% increase in nuclear guanylate cyclase activity. With nuclei isolated from glucagon-treated rats, no significant increase in enzyme activity was observed; maximal stimulation of nuclear guanylate cyclase by cAMP probably occurred at levels that are obtained in vivo after glucagon administration. Hepatic nuclear cGMP content may be regulated by a specific organelle guanylate cyclase, and cAMP may be 1 determinant of this enzyme''s activity.