GLUT4 is internalized by a cholesterol-dependent nystatin-sensitive mechanism inhibited by insulin. Academic Article uri icon

Overview

abstract

  • Insulin slows GLUT4 internalization by an unknown mechanism. Here we show that in unstimulated adipocytes, GLUT4 is internalized by two mechanisms. Approximately 80% of GLUT4 is internalized by a mechanism that is sensitive to the cholesterol-aggregating drug nystatin, and is independent of AP-2 clathrin adaptor and two putative GLUT4 endocytic motifs. The remaining GLUT4 is internalized by an AP-2-dependent, nystatin-resistant pathway that requires the FQQI GLUT4 motif. Insulin inhibits GLUT4 uptake by the nystatin-sensitive pathway and, consequently, GLUT4 is internalized by the AP-2-dependent pathway in stimulated adipocytes. The phenylalanine-based FQQI GLUT4 motif promotes AP-2-dependent internalization less rapidly than a tyrosine-based motif, the classic form of aromatic-based motifs. Thus, both a change in the predominant endocytosis pathway and the specific use of a suboptimal internalization motif contribute to the slowing of GLUT4 internalization in insulin-stimulated adipocytes. Insulin also inhibits the uptake of cholera-toxin B, indicating that insulin broadly regulates cholesterol-dependent uptake mechanisms rather than specially targeting GLUT4. Our work thus identifies cholesterol-dependent uptake as a novel target of insulin action in adipocytes.

publication date

  • November 30, 2006

Research

keywords

  • Cholesterol
  • Endocytosis
  • Glucose Transporter Type 4
  • Insulin
  • Nystatin

Identity

PubMed Central ID

  • PMC1698906

Scopus Document Identifier

  • 33845688698

Digital Object Identifier (DOI)

  • 10.1038/sj.emboj.7601462

PubMed ID

  • 17139247

Additional Document Info

volume

  • 25

issue

  • 24