Developmental Alteration in Adrenergic Regulation of Hepatic Glycogen Phosphorylase

Abstract

Abstract-The effects of development upon adrenergic regulation of glycogenolysis were characterized using isolated hepatocytes from 3 different age groups of male rats (6 week-old, 8 week-old and 30 week-old).The phosphorylase a response in isolated hepatocytes to alpha-adrenergic stimulation decreased moderately with advancing age; whereas, that to beta-adrenergic stimulation declined more rapidly and almost disappeared at the age of 30 weeks. This developmental alteration in relative contribution of alpha and beta-adrenergic regulation of phosphorylase was further confirmed by the experiments with specific antagonists. Also, the dramatic decrease of beta-adrenergic response on glycogen phosphorylase activity was found to be closely associated with a similar change of cAMP generation. In addition, the glucagon effect on cAMP production was found to be declined with advancing animal age. These results demonstrate that the glycogenolytic response of isolated rat hepatocytes to catecholamines can be mediated by different pathways according to the age of the animal; thus, juvenile male rats exhibit both the alpha and beta-adrenergic mechanism for activation of phosphorylase and the maturation is associated with a modest decline of alpha receptor-mediated effect and a dramatic attenuation of a beta-adrenergic/cAMP response.The regulation of liver glycogen me tabolism is one of the factors which plays an important role in the control of carbohydrate metabolism (1). The rate-limiting enzyme for the regulation of glycogenolysis is glycogen phosphorylase.This enzyme exists in an interconvertible active and inactive form and are controlled by a variety of hormones and neural stimulation (2, 3). In particular, catecholamines and glucagon have profound effects on the process (4).Hepatic glycogenolysis induced by catecholamines occur through both alpha and beta-adrenergic receptor mediated pathways (4, 5). The beta-adrenergic activation of glycogen phosphorylase is blocked by propranolol and is presumed to result from an increase of intracellular cAMP. The alpha-adrenergic pathway, on the other hand, activates phosphorylase without detectable increases in intracellular cAMP levels or the activation of cAM P-dependent protein kinase, and is effectively blocked by phentolamine, phenoxybenzamine and prazosin, but is unaffected by propranolol. According to the current lines of evidence, the alpha-receptors governing hepatic glycogenolysis in isolated rat hepatocytes belong to the alpha, -subclass (6, 7), and this alpha-adrenergic receptor-mediated pathway involves a rise in cytosolic Ca2+ which will stimulate phosphorylase kinase and lead to the activation of glycogen phosphorylase (8 10). (18)(19)(20).Developmental maturity and the aging process have been known to be associated with reduced responsiveness of the hepatic beta-adrenergic receptor/cAM P system as reflected in assays of adenylate cyclase activity and cAM P accumulation (21-24).In addition, the alpha-adrenergic receptor-mediated pathway has been known to predomina...