Dataset Information

Rapid delivery of internalized signaling receptors to the somatodendritic surface by sequence-specific local insertion.

ABSTRACT: The recycling pathway is a major route for delivering signaling receptors to the somatodendritic plasma membrane. We investigated the cell biological basis for the remarkable selectivity and speed of this process. We focused on the mu-opioid neuropeptide receptor and the beta(2)-adrenergic catecholamine receptor, two seven-transmembrane signaling receptors that traverse the recycling pathway efficiently after ligand-induced endocytosis and localize at steady state throughout the postsynaptic surface. Rapid recycling of each receptor in dissociated neuronal cultures was mediated by a receptor-specific cytoplasmic sorting sequence. Total internal reflection fluorescence microscopy imaging revealed that both sequences drive recycling via discrete vesicular fusion events in the cell body and dendritic shaft. Both sequences promoted recycling via "transient"-type events characterized by nearly immediate lateral spread of receptors after vesicular insertion resembling receptor insertion events observed previously in non-neural cells. The sequences differed in their abilities to produce distinct "persistent"-type events at which inserted receptors lingered for a variable time period before lateral spread. Both types of insertion event generated a uniform distribution of receptors in the somatodendritic plasma membrane when imaged over a 1 min interval, but persistent events uniquely generated a punctate surface distribution over a 10 s interval. These results establish sequence-directed recycling of signaling receptors in CNS neurons and show that this mechanism has the ability to generate receptor-specific patterns of local surface distribution on a timescale overlapping that of rapid physiological signaling.

SUBMITTER: Yu YJ

PROVIDER: S-EPMC2943418 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Rapid delivery of internalized signaling receptors to the somatodendritic surface by sequence-specific local insertion.

Yu Y Joy YJ Dhavan Rani R Chevalier Michael W MW Yudowski Guillermo A GA von Zastrow Mark M

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100901 35

The recycling pathway is a major route for delivering signaling receptors to the somatodendritic plasma membrane. We investigated the cell biological basis for the remarkable selectivity and speed of this process. We focused on the mu-opioid neuropeptide receptor and the beta(2)-adrenergic catecholamine receptor, two seven-transmembrane signaling receptors that traverse the recycling pathway efficiently after ligand-induced endocytosis and localize at steady state throughout the postsynaptic sur ...[more]

PMID: 20810891

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Project description:The δ opioid receptor (δR) is a promising alternate target for pain management because δR agonists show decreased abuse potential compared with current opioid analgesics that target the μ opioid receptor. A critical limitation in developing δR as an analgesic target, however, is that δR agonists show relatively low efficacy in vivo, requiring the use of high doses that often cause adverse effects, such as convulsions. Here we tested whether intracellular retention of δR in sensory neurons contributes to this low δR agonist efficacy in vivo by limiting surface δR expression. Using direct visualization of δR trafficking and localization, we define a phosphatase and tensin homolog (PTEN)-regulated checkpoint that retains δR in the Golgi and decreases surface delivery in rat and mice sensory neurons. PTEN inhibition releases δR from this checkpoint and stimulates delivery of exogenous and endogenous δR to the neuronal surface both in vitro and in vivo PTEN inhibition in vivo increases the percentage of TG neurons expressing δR on the surface and allows efficient δR-mediated antihyperalgesia in mice. Together, we define a critical role for PTEN in regulating the surface delivery and bioavailability of the δR, explain the low efficacy of δR agonists in vivo, and provide evidence that active δR relocation is a viable strategy to increase δR antinociception.SIGNIFICANCE STATEMENT Opioid analgesics, such as morphine, which target the μ opioid receptor (μR), have been the mainstay of pain management, but their use is highly limited by adverse effects and their variable efficacy in chronic pain. Identifying alternate analgesic targets is therefore of great significance. Although the δ opioid receptor (δR) is an attractive option, a critical limiting factor in developing δR as a target has been the low efficacy of δR agonists. Why δR agonists show low efficacy is still under debate. This study provides mechanistic and functional data that intracellular localization of δR in neurons is a key factor that contributes to low agonist efficacy, and presents a proof of mechanism that relocating δR improves efficacy.

Dataset Information

Rapid delivery of internalized signaling receptors to the somatodendritic surface by sequence-specific local insertion.

Publications

Rapid delivery of internalized signaling receptors to the somatodendritic surface by sequence-specific local insertion.

Similar Datasets

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