Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain

Jiménez-Vargas, Nestor N.; Gong, Jing; Wisdom, Matthew; Jensen, Dane D.; Latorre, Rocco; Hégron, Alan; Teng, Shavonne; DiCello, Jesse J.; Rajasekhar, Pradeep; Veldhuis, Nicholas A.; Carbone, Simona; Yu, Yang; López-López, Cintya; Jaramillo-Polanco, Josue; Canals, Meritxell; Reed, David E.; Lomax, Alan E.; Schmidt, Brian L.; Leong, Kam W.; Vanner, Stephen; Halls, Michelle L.; Bunnett, Nigel W.; Poole, Daniel P.

doi:10.1073/pnas.2000500117

Cited by 76 publications

(58 citation statements)

References 56 publications

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“…Ultimately, while receptor sequestration shuts down signaling at the plasma membrane, it might open up new therapeutic opportunities. A recent article by Jimenez-Vargas showed that SNC80 and DADLE ([D-Ala 2 , D-Leu 5 ]-Enkephalin), both of which strongly internalize DOR, activate G αi/o in endosomes and recruit β-arrestin 1/2 both to the plasma membrane and endosomes [ 104 ]. Furthermore, nanoparticle-encapsulated agonists (DADLE) target endosomal DOR and provide long-lasting antinociception through the long-lasting inhibition of mechanically evoked activation of colonic nociceptors, providing evidence that DOR in endosomes might be a superior therapeutic target for inflammatory pain [ 104 ].…”

Section: Biased Agonism On Dormentioning

confidence: 99%

Biased Opioid Ligands

2020

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Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.

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Section: Biased Agonism On Dormentioning

confidence: 99%

Biased Opioid Ligands

2020

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“…A prominent example of this difference has been shown for the parathyroid hormone receptor: modulation of this receptor by short-acting or long-acting parathyroid hormones leads to acute or sustained cAMP generation, leading to either an acute or prolonged hypercalcemic state in mice [32,33]. Sustained signaling has also been shown to be responsible for pain sensation and analgesia through the neurokinin 1 receptor and d-opiod receptors [34,35]. As additional physiological consequences for sustained signaling within endosomes are discovered, one can already envision that specifically targeting this late phase of G protein signaling may potentially impart spatial and temporal 'bias' to the types of responses elicited.…”

Section: Concluding Remarks and Perspectivementioning

confidence: 99%

Signaling at the endosome: cryo‐EM structure of a GPCR–G protein–beta‐arrestin megacomplex

Nguyen

Lefkowitz

2021

The FEBS Journal

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G-protein coupled receptors (GPCRs) are a large class of cell-surface receptor involved in cellular signaling that are currently the target of over one third of all clinically approved therapeutics. Classically, an agonist-bound, active GPCR couples to and activates G proteins through the receptor intracellular core. To attenuate G protein signaling, the GPCR is phosphorylated at its C-terminal tail and/or relevant intracellular loops, allowing for the recruitment of βarrestins (βarrs). βarrs then couple to the receptor intracellular core in order to mediate receptor desensitization and internalization. However, our lab and others have observed that some GPCRs are capable of continuously signaling through G protein even after internalization. This mode of sustained signaling stands in contrast with our previous understanding of GPCR signaling, and its molecular mechanism is still not well understood. Recently, we have solved the structure of a GPCR-G protein-βarr megacomplex by cryo-electron microscopy (cryo-EM). This 'megaplex' structure illustrates the independent and simultaneous coupling of a G protein to the receptor intracellular core, and binding of a βarr to a phosphorylated receptor C-terminal tail, with all three components maintaining their respective canonically active conformations. The structure provides evidence for the ability of a GPCR to activate G protein even while being bound to and internalized by βarr. It also reveals that the binding of G protein and βarr to the same GPCR is not mutually exclusive, and raises a number of future questions to be answered regarding the mechanism of sustained signaling.

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“…One explanation for the failure of previous drug discovery programs targeting the NK 1 R for chronic pain is that they have only targeted plasma-membrane-localized NK 1 R. Until very recently, GPCRs were only considered to be active at the cell surface, and therefore most drugs targeting GPCRs are not required to cross the plasma membrane. There is now clear evidence to show that activation of receptors in endosomes (compared with the cell surface) encodes for distinct physiological outcomes ( 5 , 8 , 49 , 50 , 51 , 52 ). It is therefore important to consider the subcellular location of a target GPCR, and whether they reside in, or are delivered to, a particular location.…”

Section: Discussionmentioning

confidence: 99%

A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes

Quynh

Shenoy

Quach

et al. 2021

Journal of Biological Chemistry

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G-protein-coupled receptors (GPCRs) are traditionally known for signaling at the plasma membrane, but they can also signal from endosomes after internalization to control important pathophysiological processes. In spinal neurons, sustained endosomal signaling of the neurokinin 1 receptor (NK 1 R) mediates nociception, as demonstrated in models of acute and neuropathic pain. An NK 1 R antagonist, Spantide I (Span), conjugated to cholestanol (Span-Chol), accumulates in endosomes, inhibits endosomal NK 1 R signaling, and causes prolonged antinociception. However, the extent to which the Chol-anchor influences long-term location and activity is poorly understood. Herein, we used fluorescent correlation spectroscopy and targeted biosensors to characterize Span-Chol over time. The Chol-anchor increased local concentration of probe at the plasma membrane. Over time we observed an increase in NK 1 R-binding affinity and more potent inhibition of NK 1 R-mediated calcium signaling. Span-Chol, but not Span, caused a persistent decrease in NK 1 R recruitment of β-arrestin and receptor internalization to early endosomes. Using targeted biosensors, we mapped the relative inhibition of NK 1 R signaling as the receptor moved into the cell. Span selectively inhibited cell surface signaling, whereas Span-Chol partitioned into endosomal membranes and blocked endosomal signaling. In a preclinical model of pain, Span-Chol caused prolonged antinociception (>9 h), which is attributable to a three-pronged mechanism of action: increased local concentration at membranes, a prolonged decrease in NK 1 R endocytosis, and persistent inhibition of signaling from endosomes. Identifying the mechanisms that contribute to the increased preclinical efficacy of lipid-anchored NK 1 R antagonists is an important step toward understanding how we can effectively target intracellular GPCRs in disease

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Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain

Cited by 76 publications

References 56 publications

Biased Opioid Ligands

Biased Opioid Ligands

Signaling at the endosome: cryo‐EM structure of a GPCR–G protein–beta‐arrestin megacomplex

A lipid-anchored neurokinin 1 receptor antagonist prolongs pain relief by a three-pronged mechanism of action targeting the receptor at the plasma membrane and in endosomes

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