Glucagon-stimulable adenylyl cyclase in rat liver. Effects of chronic uremia and intermittent glucagon administration.

Abstract

Astract. 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 < 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-Tyr'0]monoiodoglucagon as a receptor probe, the number of high affinity glucagon-binding sites was reduced 28% (P < 0.01) in uremic as compared with control liver membranes. However, the affinity ofthese 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 ,g) injections administered at 8-h intervals to normal rats reproduced all ofthe above described effects ofchronic experimental uremia on the adenylyl cyclase system. It is concluded that changes in the hormone-stimulable adAddress all reprint requests to Dr. Garber.Receivedfor publication 22 December 1982 and in revisedform 29 December 1983. enylyl 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 glucagontreated 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. IntroductionAbnormal carbohydrate metabolism is a frequent concomitant of chronic renal disease (1-3). As the result, in part, of the diminished renal clearance of glucagon, hyperglucagonemia is frequently observed in renal insufficiency (4, 5). These increased immunoreactive glucagon levels result from increases in a number of molecular weight species, each of which may have glucagon-like immunoreactivity if not biological activity (6-8). Glucagon-stimulable adenylyl cyclase activity in liver of uremic rats has been found to be increased (9, 10). Other more indirect assessments have inferred a decreased activity of this enzyme in chronic uremia (1 1). In light of these discordant data and to determine the impact of the uremic state on the hormone-stimulable adenylyl cyclase complex, we have used a monoiodinated glucagon as a probe of glucagon receptor density and affinity in membrane p...

Glucagon receptors

“…In rodents, conditions leading to a sustained elevation of plasma glucagon concentration such as glucagon treatment, fasting, liver regeneration induced by partial hepatectomy and, at least in some studies [96,97], streptozotocin-induced diabetes, are generally associated with a decrease in GR number in hepatocytes and liver membranes, suggesting that glucagon is negative regulator of the expression of the GR protein in liver (reviewed in [4]). Conversely, liver GR number has been shown to progressively increase in rats during the first month of life in the face of decreasing plasma glucagon [98].…”