Regulation of asialoglycoprotein receptor activity by a novel inactivation/reactivation cycle. Receptor reactivation in permeable rat hepatocytes is mediated by fatty acyl coenzyme A.
We previously reported that a subpopulation of asialoglycoprotein receptors (ASGP-Rs), designated State 2 ASGP-Rs, can be inactivated in digitonin-permeabilized hepatocytes in the absence of cytosol by a process that is temperature- and ATP-dependent (Medh, J. D., and Weigel, P. H. (1991) J. Biol. Chem. 266, 8771-8778). Here we show that these inactivated ASGP-Rs are reactivated by the sole addition of fatty acyl-CoA. Of the derivatives tested (acyl chain length 4-18), palmitoyl-CoA was the most effective, although stearoyl-CoA (C18) and myristoyl-CoA (C14) were also active. Lauroyl-CoA (C12) was about half as effective as palmitoyl-CoA, and decanoyl-CoA (C10) and butyl-CoA (C4) were inactive. ASGP-R reactivation did not take place in the presence of free palmitate and coenzyme A, but did occur if low levels of ATP were also added to drive palmitoyl-CoA synthesis by the permeable cells. Addition of ATP after ASGP-R reactivation with palmitoyl-CoA again resulted in a rapid inactivation of these receptors. The extent and rate of this second ASGP-R inactivation process were proportional to ATP concentration; half-maximal effects occurred at approximately 0.5 mM ATP. ATP also rapidly reversed the ASGP-R reactivation seen with the other fatty acyl-CoAs. The results demonstrate the existence of a previously unrecognized pathway that regulates the activity of the ASGP-R population responsible for the majority of ligand endocytosis and processing in hepatocytes. This novel receptor inactivation/reaction cycle could ensure the high efficiency of segregating ligand and receptor during endocytosis and receptor recycling.
Weigel
P H
PH
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 77555-0647.
Oka
J A
JA
D000214:Acyl Coenzyme A / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D037263:Asialoglycoprotein Receptor; D002478:Cells, Cultured; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*
D000214:Acyl Coenzyme A; D037263:Asialoglycoprotein Receptor; D011956:Receptors, Cell Surface; D000255:Adenosine Triphosphate