Understanding Periperal Membrane Protein Interactions | BPS Thematic Meeting

Understanding Peripheral Membrane Protein Interactions: Structure, Dynamics, Function and Therapy

Wednesday Speaker Abstracts

STRUCTURAL UNDERSTANDING OF G PROTEIN GA3NG OF K+ CHANNELS IN BRAIN AND HEART Diomedes E. Logothetis 2 ; Liang Wang 1 ; Takeharu Kawano 2 ; Georgios Skiniotis 1 ; 1 St. Jude Children's Research Hospital, Department of Structural Biology, Memphis, TN, USA 2 Northeastern University, Pharmaceutical Sciences, Boston, MA, USA GTP-binding (G) protein gated potassium (K + ) channels (4 members) belong to the family of Inwardly Rectifying (IR) channels (16 members). They are commonly referred to as Kir1-4 (K inwardly rectifying) or GIRK1-4 (G protein inwardly rectifying K) channels. GIRK2 and GIRK4 can form functional homotetramers, while GIRK1 and GIRK3 can only form functional heterotetramers with the GIRK2 and GIRK4 subunits. All four GIRK subunits are expressed in neuronal tissues, while in non-neuronal tissues, expression of GIRK2 and GIRK3 is rather limited. The beta-gamma subunits of G proteins, the Gbg dimer, binds the cytosolic domains of GIRK channels to stimulate their activity. Our study methods included, microscopy, (cryo electron, TIRF, etc.), Molecular Dynamics (MD) simulations, electrophysiology (patch clamp, TEVC), and molecular biology (mutagenesis). Thus, we found that signaling through opioid or GABA B receptors in the brain can activate G proteins and stimulate the activity of GIRK1/2 heterotetramers via the Gbg dimer in nociceptive neurons that quiets them down and relieves pain but at the same time disinhibits dopaminergic neurons and induces addiction by causing excess dopamine release. Similarly, signaling through muscarinic M2 receptors in the heart mediates the slowing down of heart rate by the parasympathetic system through the vagus nerve. The structural basis of regulation of the activity of GIRK channels in brain and heart by G proteins and by direct channel activators has started to be elucidated by atomic resolution structures of GIRK channels with and without their activators. Key to this regulation of channel activity is the participation of the signaling phospholipid phosphatidylinositol 4,5 bis-phosphate (PIP 2 ) which through electrostatic interactions stabilizes the gates in the open structure.

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