BIPHASIC INTRACELLULAR REDISTRIBUTION OF ALPHA-1-ADRENERGIC RECEPTORS IN RAT-LIVER DURING SEPSIS

Changes in the distribution of alpha1-adrenergic receptors in two subcellular fractions, the plasma membrane and the light vesicle, of rat liver during sepsis were studied using [H-3]prazosin binding and photoaffinity labeling with [I-125]arylazidoprazosin in combination with sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Sepsis was induced by cecal ligation and puncture (CLP). Septic rats exhibit two metabolically distinct phases: an initial hypermetabolic (hyperglycemic) phase (9 h after CLP; early sepsis) followed by a hypometabolic (hypoglycemic) phase (18 h after CLP; late sepsis). [H-3]prazosin binding studies show that during early sepsis, the maximal binding capacity (B(max)) was increased by 35% in plasma membranes but was decreased by 28% in light vesicles; while during late sepsis, the B(max) was decreased by 30% in plasma membranes but was increased by 33% in light vesicles. The photoaffinity labeling studies revealed two major binding peptides with M(r) of 77,000 and 68,000 Da and one minor binding protein with M(r) of 39,000 Da. The total binding for the three labeled peptides during early sepsis was increased by 26% in plasma membranes but was decreased by 33% in light vesicles, while during late sepsis the total binding was decreased by 19% in plasma membranes but was increased by 35% in light vesicles. These data indicate that alpha1-adrenergic receptors in the rat liver were externalized from light vesicles to plasma membranes during the hyperglycemic phase while they were internalized from surface membranes to intracellular sites during the hypoglycemic phase of sepsis. Because alpha1-adrenergic receptor mediation regulates hepatic glucose output into the circulation, a biphasic intracellular redistribution of alpha1-adrenergic receptors in the liver may contribute to the hepatic glucose dyshomeostasis during various phases of sepsis.