The Logothetis lab focuses on regulation of ion channel activity by mechanisms that are confined to the plasma membrane, namely by phosphoinositide and G protein signaling. This seminar will focus on recent advances we have made in understanding G protein signaling to ion channels and also through heteromeric G protein-coupled receptors.
Phosphoinositides, and in particular phosphatidylinositol 4,5 bisphosphate (PIP2), are required for most ion channels to maintain their activity. Inwardly rectifying Potassium (Kir) channels have been co-crystallized with PIP2 and by employing Molecular Dynamics (MD) simulations, we are starting to understand how lipid-protein interactions stabilize the open state of these channels.
G protein coupled receptor (GPCR) activation by agonists activates heterotrimeric G proteins (Gá and Gâã) to interact with effector proteins to regulate their activity. Back in 1987 we showed that the Gâã subunits activate the Kir3 channels in heart but how the protein-protein interactions lead to stabilization of the open channel state has yet to be elucidated. Our computational models, of how Gâã stabilizes the channel open state are supported by experimental tests, are starting to reveal the mechanism of G protein regulation of Kir3 channel activity. Unpublished results in planar lipid bilayers show successful reconstitution of the entire signaling complex (GPCR, G proteins, and Kir3 channel), providing strong evidence for a critical role of the GPCR and the Gá subunit in the signaling to the K+ channel.
Signaling by heteromeric GPCR receptors is not well understood. We studied the signaling properties of the heteromeric complex of the serotonin (5-HT2A) and the metabotropic glutamate (mGlu2) receptors and compared them to the signaling properties of its homomeric parts. This signaling complex has been implicated in psychosis and schizophrenia and ligands that target each of its GPCR components either prevent or exacerbate psychosis. Using Kir channels as reporters of the GPCR activity we discovered an inverse conformational coupling of the two GPCRs, where the activated state of one receptor caused an inactive state of the other and vice versa. The physiological state of this GPCR complex is such that Gi signaling through the mGlu2R is enhanced at the expense of Gq signaling through the 5-HT2AR. In psychosis, this Gi signaling advantage through this GPCR complex is reduced and drugs that restore it serve as antipsychotics. Thus, inverse agonists of the 5-HT2AR (e.g. Clozapine or Risperidone) or strong agonists of mGlu2R (e.g. LY379268 or LY2140023) are being used as antipsychotics. The details of the inverse conformational coupling of heteromeric GPCRs as well as the connection of their signaling to the psychotic phenotype remain open areas of investigation that promise to provide clues as to the biological basis of schizophrenia.
Speaker: Diomedes E. Logothetis
Virginia Commonwealth University, School of Medicine
Department of Physiology and Biophysics
Time: Thursday, 28 February 2013, 11:00