Seminar by Diego Krapf from Colorado State University (Fort Collins, Colorado, USA)
Hosted by Prof Maciej Lewenstein
Opioid receptors are responsible for the analgesic effects of exogenously administered opioids (e.g. morphine, codeine, fentanyl). Assays to understand different properties of opioid receptor targeting drugs largely depend on the output of specific effectors, but effector-level readouts do not account for the heterogeneity of receptor states in response to a drug. One way to study the heterogeneity in receptor activity and dynamics in living cells is via single-particle tracking, which facilitates the study of subpopulations of receptors otherwise invisible to effector-based readouts such as electrophysiology. In this study, the dynamics of mu-opioid receptors (MOR) was investigated in response to receptor-targeting drugs. A quantitative analysis of MOR trajectories shows that receptors can be found in both immobile and mobile states under basal conditions. Investigation of receptors in the mobile state revealed transient confinement influenced by G-protein binding. Complex dynamics involving anomalous diffusion governed by this intermittent process were observed. Furthermore, most trajectories violate the ergodic hypothesis, a phenomenon manifested as substantial differences between the time-averaged and the ensemble-averaged mean squared displacements. Ergodicity breaking was found to be caused by the receptor transient confinement with a heavy-tailed distribution of dwell times in this state, which in turn is affected by agonist exposure.