The effects of chronic
uremia and
glucagon administration on
glucagon-stimulable
adenylyl cyclase in rat liver were assessed by determinations of
adenylyl cyclase activities, specific
iodoglucagon binding, and the activity of the stimulatory regulatory component of
adenylyl cyclase.
Glucagon-stimulated
adenylyl cyclase was reduced in
uremia to 75-80% of control levels (P less than 0.05), in the presence or absence of saturating levels of
guanosine triphosphate (
GTP) and 5'-guanylylimidodiphosphate [
GMP-P(NH)P]. Although these changes were accompanied by a concomitant 20% reduction in
sodium fluoride-stimulated activity, basal,
GTP-,
GMP-P(NH)P-, and
manganese-dependent
adenylyl cyclase activities were unchanged. Using [125I-Tyr10]
monoiodoglucagon as a receptor probe, the number of high affinity
glucagon-binding sites was reduced 28% (P less than 0.01) in uremic as compared with control liver membranes. However, the affinity of these binding sites was unaltered. The S49 cyc- -reconstituting activity with respect to both
GMP-P(NH)P- and
isoproterenol plus
GTP-stimulable
adenylyl cyclase was unaltered in membranes from uremic as compared with control rats. Intermittent
glucagon (80-100 micrograms)
injections administered at 8-h intervals to normal rats reproduced all of the above described effects of chronic experimental
uremia on the
adenylyl cyclase system. It is concluded that changes in the
hormone-stimulable
adenylyl cyclase complex in
uremia and with
glucagon treatment result primarily from a decrease in the number of
hormone-specific receptor sites in hepatic plasma membranes. Since the changes in liver
adenylyl cyclase are qualitatively and quantitatively the same in
glucagon-treated and uremic rats, it is suggested that these may be the result of the hyperglucagonemia of
uremia. Further, the data reveal an unexpected dissociation between
guanine nucleotide and
sodium fluoride stimulation of
adenylyl cyclase. Possible causes for this dissociation based on the known subunit composition of cyclase coupling
proteins are discussed.