Regulation of glycogen metabolism in hepatocytes through adenosine receptors. Role of Ca 2+ and cAMP

Abstract

The objective of this work is to identify the adenosine receptor subtype and the triggered events involved in the regulation of hepatic glycogen metabolism. Glycogenolysis, gluconeogenesis, cAMP, and cytosolic Ca 2+ ([Ca 2+] cyt) were measured in isolated hepatocytes challenged with adenosine A 1, A 2A, and A 3 receptor-selective agonists. Stimulation of adenosine receptor subtypes with selective agonists in Ca 2+ media produced a dose-dependent increase in [Ca 2+] cyt with A 1>A 2A=A 3, cAMP with A 2A, glycogenolysis with A 1>A 2A>A 3, and gluconeogenesis with A 2A>A 1>A 3, in addition, a decrease in cAMP was observed with A 1=A 3. Comparatively, in Ca 2+-free media or with a cell membrane-permeant Ca 2+ chelator, activation of these adenosine receptors with the same selective agonists produced a smaller and transient rise in [Ca 2+] cyt with A 1=A 3>A 2, no rise in glycogenolysis and gluconeogenesis with A 3>A 1, but a full rise with A 2A. Thus, in isolated rat hepatocytes activation of the adenosine A 1 receptor triggered Ca 2+-mediated glycogenolysis, activation of the adenosine A 2A receptor stimulated cAMP-mediated gluconeogenesis, and activation of the adenosine A 3 receptor increased [Ca 2+] cyt and decreased cAMP with minor changes in glycogen metabolism.