Disruption of Pancreatic β-Cell Lipid Rafts Modifies Kv2.1 Channel Gating and Insulin Exocytosis

• Published in: The Journal of biological chemistry Vol. 279; no. 23; p. 24685
• Main Authors: Fuzhen Xia, Xiaodong Gao, Edwin Kwan, Patrick P. L. Lam, Lillian Chan, Keiyan Sy, Laura Sheu, Michael B. Wheeler, Herbert Y. Gaisano, Robert G. Tsushima
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 04.06.2004
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M314314200

In pancreatic β-cells, the predominant voltage-gated Ca 2+ channel (Ca V 1.2) and K + channel (K V 2.1) are directly coupled to SNARE (soluble N -ethylmaleimide-sensitive factor attachment protein (SNAP) receptor) proteins. These SNARE proteins modulate channel expression and gating and closely associate these channels with the insulin secretory vesicles. We show that K V 2.1 and Ca V 1.2, but not K V 1.4, SUR1, or Kir6.2, target to specialized cholesterol-rich lipid raft domains on β-cell plasma membranes. Similarly, the SNARE proteins syntaxin 1A, SNAP-25, and VAMP-2, but not Munc-13-1 or n-Sec1, are associated with lipid rafts. Disruption of the lipid rafts by depleting membrane cholesterol with methyl-β-cyclodextrin shunts K V 2.1, Ca V 1.2, and SNARE proteins out of lipid rafts. Furthermore, methyl-β-cyclodextrin inhibits K V 2.1 but not Ca V 1.2 channel activity and enhances single-cell exocytic events and insulin secretion. Membrane compartmentalization of ion channels and SNARE proteins in lipid rafts may be critical for the temporal and spatial coordination of insulin release, forming what has been described as the excitosome complex.