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Desensitization of mu-opioid receptor-evoked potassium currents: initiation at the receptor, expression at the
Christophe Blanchet1, Christian Lüscher
1Pharmacology, Department of Physiology, and Neurology, University of Geneva, CH 1211 Geneva, Switzerland.
Abstract:
Many G protein-coupled receptor-mediated responses desensitize within minutes. Sustained stimulation of mu-opioid receptors (MORs), which primarily signal through G(i/o) proteins, leads to activation and subsequent desensitization of G protein-coupled inwardly rectifying potassium (GIRK) currents. We observed that in neurons of the locus coeruleus, which express among the highest levels of MORs in the brain, the degree of desensitization depended on the intensity of receptor stimulation, indicating that the process is initiated at the receptor. Interestingly, while GIRK-mediated postsynaptic inhibition substantially desensitized within 15 min, presynaptic inhibition of afferent transmission, which involves other effector systems, remained constant, suggesting that the postsynaptic desensitization we observed is expressed at the effector. We show that desensitized GIRK currents can gradually be reactivated by additional G protein signals of increasing intensity and present evidence that desensitization is a G protein-mediated process. Finally, desensitization of MOR-induced GIRK currents had heterologous effects on responses mediated by other G protein-coupled receptors converging onto the same population of GIRK channels. Taken together, our results provide evidence for a form of desensitization mediated by a slowly developing G protein-dependent pathway, initiated at the MORs and leading to competitive inhibition of GIRK channel activation. This implies that MORs exert a bidirectional action on GIRK channels.
Insights
Sustained stimulation of mu-opioid receptors (MORs) desensitizes G protein-coupled inwardly rectifying potassium (GIRK) currents. This desensitization is G protein-mediated and can be overcome by stronger signals, impacting other receptors.
Area of Science:
- Neuroscience
- Molecular Pharmacology
- Cell Signaling
Background:
- G protein-coupled receptor (GPCR) signaling is crucial for neuronal function.
- Mu-opioid receptors (MORs) are key GPCRs involved in pain and reward pathways.
- Desensitization is a common mechanism limiting GPCR response duration.
Purpose of the Study:
- To investigate the desensitization mechanisms of G protein-coupled inwardly rectifying potassium (GIRK) currents activated by MORs.
- To determine if MOR desensitization is initiated at the receptor and expressed at the effector level.
- To explore the role of G protein signaling intensity in GIRK current reactivation and heterologous effects.
Main Methods:
- Electrophysiological recordings in locus coeruleus neurons.
- Stimulation of mu-opioid receptors (MORs) with varying intensities.
- Analysis of G protein-coupled inwardly rectifying potassium (GIRK) current kinetics and desensitization.
- Investigation of cross-talk between different GPCRs converging on GIRK channels.
Main Results:
- MOR stimulation intensity dictates the degree of GIRK current desensitization.
- Postsynaptic GIRK current desensitization occurs rapidly, while presynaptic effects remain stable.
- Desensitized GIRK currents can be reactivated by increased G protein signaling intensity.
- MOR desensitization exhibits heterologous effects on other GPCR-mediated responses via GIRK channels.
Conclusions:
- MOR desensitization is a G protein-dependent process initiated at the receptor.
- A slowly developing pathway mediates MOR-induced GIRK current desensitization, leading to competitive inhibition of channel activation.
- MORs exert bidirectional control over GIRK channels, influencing both direct and heterologous signaling pathways.