Cholesterol modulation of nicotinic acetylcholine receptor endcytosis

BORRONI M.V; BARRANTES F.J

Washington

Congreso; Neuroscience 2011; 2011

Society for neuroscience

The number and stability of nicotinic acetylcholine receptors (AChR) at the cell surface is key to the correct functioning of the cholinergic synapse. Cholesterol is necessary for homeostasis of AChR levels at the plasmalemma and for ion translocation (reviewed in Barrantes, Subcel. Biochem.51: 467-487 (2010)). We have found that the endocytic pathway followed by muscle-type AChR in cholesterol-depleted cells (Chol-) is different from that in control cells. Under Chol- conditions, the receptor is internalized by a ligand-, clathrin- and dynamin-independent mechanism, whereas in control CHO cells or in C2C12 myotubes the AChR requires ligand binding to initiate internalization (Kumari et al., J. Cell Biol. 181: 1171-1193 (2008)). Expression of a dominant negative form of the small GTPase Rac1, Rac1N17, abrogates receptor endocytosis. The accelerated AChR internalization proceeds even upon disruption of the actin cytoskeleton, at variance with control cells (Kumari et al., 2008). AChR internalization under Chol- conditions is furthermore found to require the activity of Arf6 and its effectors Rac1 and phospholipase D. The Arf6-dependent mechanism may constitute the default endocytic pathway followed by the AChR in the absence of external ligands, membrane Chol levels acting as a key homeostatic regulator of cell surface receptor levels (Borroni & Barrantes, J. Biol. Chem. 286: 17122-17132 (2011).