Convergent, functionally independent signaling by mu and delta opioid receptors in hippocampal parvalbumin interneurons

Functional interactions between G protein-coupled receptors are poised to enhance neuronal sensitivity to neuromodulators and therapeutic drugs. Mu and Delta opioid receptors (MORs and DORs) can interact when overexpressed in the same cells, but whether co-expression of endogenous MORs and DORs in neurons leads to functional interactions is unclear. Here, in mice, we show that both MORs and DORs inhibit parvalbumin-expressing basket cells (PV-BCs) in hippocampal CA1 through partially occlusive signaling pathways that terminate on somato-dendritic potassium channels and presynaptic calcium channels. Using photoactivatable opioid neuropeptides, we find that DORs dominate the response to enkephalin in terms of both ligand-sensitivity and kinetics, which may be due to relatively low expression levels of MOR. Opioid-activated potassium channels do not show heterologous desensitization, indicating that MORs and DORs signal independently. In a direct test for heteromeric functional interactions, the DOR antagonist TIPP-Psi does not alter the kinetics or potency of either the potassium channel or synaptic responses to photorelease of the MOR agonist DAMGO. Thus, aside from largely redundant and convergent signaling, MORs and DORs do not functionally interact in PV-BCs in a way that impacts somato-dendritic potassium currents or synaptic transmission. These findings imply that crosstalk between MORs and DORs, either in the form of physical interactions or synergistic intracellular signaling, is not a preordained outcome of co-expression in neurons.

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Convergent, functionally independent signaling by mu and delta opioid receptors in hippocampal parvalbumin interneurons

10.1101/2021.04.23.441199 ◽

2021 ◽

Author(s):

Xinyi Jenny He ◽

Janki Patel ◽

Connor E. Weiss ◽

Xiang Ma ◽

Brenda L. Bloodgood ◽

...

Keyword(s):

Potassium Channels ◽

Opioid Receptors ◽

Intracellular Signaling ◽

Functional Interactions ◽

Therapeutic Drugs ◽

Delta Opioid Receptors ◽

Hippocampal Ca1 ◽

Heterologous Desensitization ◽

Physical Interactions ◽

Presynaptic Calcium

AbstractFunctional interactions between G protein-coupled receptors are poised to enhance neuronal sensitivity to neuromodulators and therapeutic drugs. Mu and Delta opioid receptors (MORs and DORs) can interact when overexpressed in the same cells, but whether co-expression of endogenous MORs and DORs in neurons leads to functional interactions is unclear. Here, we show that both MORs and DORs inhibit parvalbumin-expressing basket cells (PV-BCs) in hippocampal CA1 through partially occlusive signaling pathways that terminate on somato-dendritic potassium channels and presynaptic calcium channels. Using photoactivatable opioid neuropeptides, we find that DORs dominate the response to enkephalin in terms of both ligand-sensitivity and kinetics, which may be due to relatively low expression levels of MOR. Opioid-activated potassium channels do not show heterologous desensitization, indicating that MORs and DORs signal independently. In a direct test for heteromeric functional interactions, the DOR antagonist TIPP-Psi does not alter the kinetics or potency of either the potassium channel or synaptic responses to photorelease of the MOR agonist DAMGO. Thus, despite largely redundant and convergent signaling, MORs and DORs do not functionally interact in PV-BCs. These findings imply that crosstalk between MORs and DORs, either in the form of physical interactions or synergistic intracellular signaling, is not a preordained outcome of co-expression in neurons.

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Heteromerization of Endogenous Mu and Delta Opioid Receptors Induces Ligand-Selective Co-Targeting to Lysosomes

Molecules ◽

10.3390/molecules25194493 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4493 ◽

Cited By ~ 1

Author(s):

Lyes Derouiche ◽

Florian Pierre ◽

Stéphane Doridot ◽

Stéphane Ory ◽

Dominique Massotte

Keyword(s):

Opioid Receptor ◽

Opioid Receptors ◽

Acid Ethyl Ester ◽

Mu Opioid Receptor ◽

Mu Opioid ◽

Therapeutic Drugs ◽

Delta Opioid Receptors ◽

The Impact ◽

Fine Tune ◽

Intracellular Fate

Increasing evidence indicates that native mu and delta opioid receptors can associate to form heteromers in discrete brain neuronal circuits. However, little is known about their signaling and trafficking. Using double-fluorescent knock-in mice, we investigated the impact of neuronal co-expression on the internalization profile of mu and delta opioid receptors in primary hippocampal cultures. We established ligand selective mu–delta co-internalization upon activation by 1-[[4-(acetylamino)phenyl]methyl]-4-(2-phenylethyl)-4-piperidinecarboxylic acid, ethyl ester (CYM51010), [d-Ala2, NMe-Phe4, Gly-ol5]enkephalin (DAMGO), and deltorphin II, but not (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80), morphine, or methadone. Co-internalization was driven by the delta opioid receptor, required an active conformation of both receptors, and led to sorting to the lysosomal compartment. Altogether, our data indicate that mu–delta co-expression, likely through heteromerization, alters the intracellular fate of the mu opioid receptor, which provides a way to fine-tune mu opioid receptor signaling. It also represents an interesting emerging concept for the development of novel therapeutic drugs and strategies.

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