The Functional Diversity of G Proteins in Opioid Receptor Signaling

Abstract ID 95565 Poster Board 354 G protein heterotrimers (Galpha, Gbeta, and Ggamma) are important signal transducers upon activation of G protein coupled receptors (GPCRs). Opioid receptors belong to the class A GPCRs and play major roles in pain, mood, reward, and motivation. Opioids are used for pain management despite the side effects that contribute to the opioid crisis. The pursuit of non-addictive opioid analgesics remains unattained due to the unresolved intricacies of opioid actions, receptor signaling cascades, and neuronal plasticity. Opioid receptor activation couples to up to seven Ga subtypes (Gai1, Gai2, Gai3, GaoA, GaoB, Gaz, and/or Gustducin). The molecular basis for the G protein subtype selectivity are largely unclear; the functional consequence of individual G protein signaling remains unknown. We thus determined the active-state structures of kappa opioid receptor (KOR) in a complex with multiple G-protein heterotrimers using cryo-electron microscopy. Comparisons of these structures reveal molecular determinants critical for KOR–G-protein interactions as well as key elements governing Gi/o-family subtype selectivity. Furthermore, the G-protein subtypes display an intrinsically different allosteric activity on agonist activity at KOR. These results provide insights into the actions of opioids and G-protein-coupling specificity at KOR and establish a foundation to examine the therapeutic potential of pathway-selective agonists of KOR. The work is supported by NIH grants R35GM143061 (to T.C.)