Differential effects of monensin on asialoglycoprotein receptor function after short-term ethanol administration.
Chronic ethanol consumption is associated with multiple impairments in receptor-mediated endocytosis (RME) by the hepatic asialoglycoprotein receptor (ASGP-R). Previous work on this receptor has shown that its activity can be perturbed by the carboxylic ionophore monensin. This agent has been shown to preferentially affect receptor-ligand dissociation and receptor redistribution of one subset (State 2) of ASGP-R, while receptor function in a second subset (State 1 receptors) is unaffected. In the present study, we examined the effect of monensin on ASGP-R activity and intracellular receptor-ligand dissociation after 7-10 days of ethanol feeding, a time when we have shown altered ASGP-R function in ethanol-fed animals. Hepatocytes from male Wistar rats (fed an ethanol-containing or control diet) were utilized. Ethanol administration decreased total ligand binding by 35-40% (P < 0.01) without a change in receptor protein content. After monensin treatment, surface receptors on cells from control animals were inactivated and redistributed to the cell interior. In cells from ethanol-fed animals, a similar pattern of monensin-induced inactivation was shown, but no redistribution occurred. Intracellular receptor-ligand dissociation was impaired in both cell types, although the monensin-induced effect on dissociation was significantly less dramatic (two-fold) in the hepatocytes from ethanol-fed animals as compared with controls. Thus, although receptors on both cell types were susceptible to monensin, cells from the ethanol-fed animals were less vulnerable to the added effects of this agent. Since monensin affects functioning of State 2, but not State 1 receptors, a very early effect of ethanol may be a preferential impairment in the State 2 receptor population.
Tworek
B L
BL
Liver Study Unit, Department of Veterans Affairs Medical Center, Omaha, NE 68105, USA.
Wiegert
R L
RL
Jeanette
J P
JP
Tuma
D J
DJ
Casey
C A
CA
D000818:Animals; D000906:Antibodies / Q000276:immunology; D037263:Asialoglycoprotein Receptor; D002478:Cells, Cultured; D000431:Ethanol / Q000008:administration & dosage*; D007457:Iodine Radioisotopes; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008985:Monensin / Q000494:pharmacology*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D037263:Asialoglycoprotein Receptor; D007457:Iodine Radioisotopes; D011956:Receptors, Cell Surface; D000431:Ethanol; D008985:Monensin