J. Biol. Chem., Vol. 255, Issue 19, 8979-8982, 10, 1980
The role of insulin, glucagon, and cAMP in the regulation of hepatocyte guanylate cyclase activity
HS Earp
Rat liver regeneration is regulated by a humoral signal that includes
insulin and a sustained elevation in glucagon. The intracellular response
is characterized by a rise in cAMP as well as altered cGMP metabolism, i.e.
increased particulate guanylate cyclase activity. To evaluate the role of
hormones in the regulation of guanylate cyclase during liver regeneration,
the enzyme activity of primary cultures of rat hepatocytes was examined.
Hepatocytes were maintained for 22 h in medium containing various
combinations of insulin, glucagon, and cAMP. The cells were then harvested
and homogenized and the guanylate cyclase activity was assessed in vitro.
Hepatocytes maintained in 100 nM insulin exhibited a 42% (p < 0.001)
increase in guanylate cyclase activity when compared to cells cultured in
medium alone. Incubation with glucagon (100 nM) produced a 52% (p <
0.01) rise. In the presence of insulin (100 nM), culturing with as little
as 5 nM glucagon resulted in increased activity, and 100 nM glucagon
produced a 161% (p < 0.001) rise above cultures maintained in insulin
alone. Thus, the combination of the two hormones produced an effect that
was significantly (p < 0.01) greater than additive. Dibutyryl cAMP and
8-bromoadenosine 3':5'- monophosphoric acid were at least as effective as
glucagon; the enzyme activity of cells maintained in 5 microM
N6,02'-dibutyryl adenosine 3':5'-monophosphoric acid and 100 nM insulin was
243% (p < 0.001) above those in insulin alone. The findings suggest that
the activity of hepatocyte guanylate cyclase is regulated by a synergistic
action of insulin and glucagon and that positive interactions between the
two cyclic nucleotide second messenger systems exist.
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