Membrane microdomain determines the specificity of receptor-mediated modulation of Kv7/M potassium currents.

Abstract The Kv7/M current is one of the major mechanisms controlling neuronal excitability, which can be modulated by activation of the G protein-coupled receptor (GPCR) via distinct signaling pathways. Membrane microdomains known as lipid rafts have been implicated in the specificity of various cell signaling pathways. The aim of this study was to understand the role of lipid rafts in the specificity of Kv7/M current modulation by activation of GPCR. Methyl-β-cyclodextrin (MβCD), often used to disrupt the integrity of lipid rafts, significantly reduced the bradykinin receptor (B 2 R)-induced but not muscarinic receptor (M 1 R)-induced inhibition of the Kv7/M current. B 2 R and related signaling molecules but not M 1 R were found in caveolin-containing raft fractions of the rat superior cervical ganglia. Furthermore, activation of B 2 R resulted in translocation of additional B 2 R into the lipid rafts, which was not observed for the activation of M 1 R. The increase of B 2 R-induced intracellular Ca 2+ was also greatly reduced after MβCD treatment. Finally, B 2 R but not M 1 R was found to interact with the IP 3 receptor. In conclusion, the present study implicates an important role for lipid rafts in mediating specificity for GPCR-mediated inhibition of the Kv7/M current.