HOW DO G-PROTEIN RECEPTORS INFLUENCE POTASSIUM CHANNELS?
City College of CUNY
Department of Chemistry
Biochemistry Seminar
Wednesday, May 3, 2000
Room J1027
11:15 AM
Diomedes E. Logothetis
Professor of Physiology and Biophysics
Mount Sinai School of Medicine Regulation of G Protein-Sensitive K+ Channels by
PIP2
Abstract
Direct interactions of phosphatidylinositol-4, 5-bisphosphate (PIP2)
with inwardly rectifying potassium channels are stronger with channels
rendered constitutively active by binding to PIP2, such as IRK1, than
with G-protein-gated channels (GIRKs). As a result, PIP2
alone can activate IRK1 but not GIRKs, which require extra gating
molecules such as the subunits of G proteins or sodium ions.
We have identified two conserved residues near the inner-membrane
interface of these channels that are critical in interactions with
PIP2. Between these two arginines, a conservative
change of isoleucine residue 229 in GIRK4 to the corresponding leucine
found in IRK1 strengthens GIRK4PIP2 interactions, eliminating the need
for extra gating molecules. A negatively charged GIRK4 residue, two
positions away from the most strongly interacting arginine, mediates
stimulation of channel activity by sodium by strengthening channelPIP2
interactions. Our results provide a mechanistic framework for
understanding how distinct gating mechanisms of inwardly rectifying
potassium channels allow these channels to subserve their physiological
roles.