Heterodimerization of human orexin receptor 1 and kappa opioid receptor promotes protein kinase A/cAMP-response element binding protein signaling via a Gαs-mediated mechanism

Chen, Jing; Zhang, Rumin; Chen, Xiaoyu; Wang, Chunmei; Cai, Xin; Liu, Haiqing; Jiang, Yunlu; Liu, Chuanxin; Bai, Bo

doi:10.1016/j.cellsig.2015.03.027

Cited by 49 publications

(50 citation statements)

References 59 publications

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“…In this study, using TM and TM‐m peptides as biochemical tools to dissect actions of the SCTR/AT1aR heteromer in PVN, we firstly demonstrate the in vivo actions of SCTR/AT1aR heteromer in regulating plasma Vp release and expression via cFos/cAMP/CREB pathway in magnocellular neurons of PVN. Our data also explain the results of previous studies indicating: 1 ) colocalization of SCTR and AT1aR in PVN, particularly in magnocellular neurons, 2) central actions of ANGII require an intact SCT‐SCTR axis, and 3) actions of the SCTR/AT1aR heteromer are largely dependent on the cAMP pathway (13, 36, 37). Of note, the functional specificity of SCTR/AT1aR heteromer was fully demonstrated by intracerebroventricular injection of STM2 because it can only disrupt SCTR/AT1aR heterodimerization but not SCTR or AT1aR homodimerization.…”

Section: Discussionsupporting

confidence: 91%

In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN

2019

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With an increasing body of evidence regarding GPCR oligomerization and its clinical implications over the last decade, the modulation and dynamics of GPCR homo‐ and hetero‐oligomers has more recently become an area of intense research focus. Previously, our lab showed in vitro heteromer formation between angiotensin II receptor type 1 subtype a (AT1aR) and secretin receptor (SCTR), which is involved in in vivo control of hyperosmolality‐induced water drinking behavior. Because the secretin (SCT)/SCTR axis is crucial to the central actions of angiotensin II (ANGII) and both SCT and ANGII are capable of triggering vasopressin (Vp) release from hypothalamus, we investigated here the in vivo role of SCTR‐AT1aR heteromer in regulating Vp release in hypothalamus using transmembrane peptides as tools. We showed that SCTR‐AT1aR heteromer mediates stimulatory actions of both SCT and ANGII in hypothalamic Vp expression and release as well as neuronal activities via the immediate early gene cFos. The results from this study not only are consistent with our hypothesis that SCT and ANGII interact at the receptor level to mediate their water homeostatic activities but also provide evidence for in vivo functions of cross‐class GPCR heteromers.—Mak, S. O. K., Zhang, L., Chow, B. K. C. In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN. FASEB J. 33, 5389–5398 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 91%

In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN

2019

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“…KOPr agonists have also been shown to stimulate appetite, food consumption, and sucrose intake due to KOPr and orexin co-localisation within synaptic vesicles in the hypothalamus (Muschamp et al 2014). The heterodimerisation (Chen et al 2015) and co-transmission of both peptides may be a mechanism by which KOPr regulates feeding (Muschamp et al 2014), a relationship that warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal B and β-tetrahydropyran Sal B, have anti-cocaine properties with minimal side effects

et al. 2017

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Rationale Kappa-opioid receptor (KOPr) agonists have pre-clinical anti-cocaine and analgesic effects. However, side-effects including sedation, dysphoria, aversion, anxiety and depression limit their therapeutic development. The unique structure of Salvinorin A has been used to develop longer-acting KOPr agonists. Objectives We evaluate two novel C-2 analogues of Salvinorin A, ethoxymethyl ether Sal B (EOM Sal B) and β-tetrahydropyran Sal B (β-THP Sal B) alongside U50,488 for their ability to modulate cocaine-induced behaviours and side-effects, pre-clinically. Methods Anti-cocaine properties of EOM Sal B were evaluated using the reinstatement model of drug-seeking in self-administering rats. EOM Sal B and β-THP Sal B were evaluated for effects on cocaine-induced hyperactivity, spontaneous locomotor activity and sucrose self-administration. EOM Sal B and β-THP Sal B were evaluated for aversive, anxiogenic and depressive-like effects using conditioned place aversion (CPA), elevated plus maze (EPM) and forced swim tests (FST) respectively. Results EOM Sal B (0.1, 0.3 mg/kg, i.p.) dose-dependently attenuated drug-seeking and EOM Sal B (0.1 mg/kg, i.p.) and β-THP Sal B (1 mg/kg, i.p.) attenuated cocaine-induced hyperactivity. No effects on locomotor activity, open arm times (EPM) or swimming behaviours (FST), were seen with EOM (0.1 or 0.3 mg/kg, i.p.) or β-THP Sal B (1 or 2 mg/kg, i.p.). However, β-THP Sal B decreased time spent in the drug-paired chamber. Conclusion EOM Sal B is more potent than Sal A and β-THP Sal B in reducing drug-seeking behaviour with fewer side-effects. EOM Sal B showed no effects on sucrose self-administration (0.1 mg/kg), locomotor, depressive-like, aversive-like or anxiolytic effects.

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“…As illustrated in Figure , as cells were exposed to 3 μM NAL, subsequent application of neither 1 μM dynorphin A 1‐13 nor 30 μM naloxone modified the current amplitude. These results suggest that NAL‐mediated inhibition of I Na in mHippoE‐14 neurons might not be linked to its binding to opioid receptors although hippocampal neurons express those receptors (Chen et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…Previous reports have suggested that μ‐ or κ‐opioid receptors may be expressed in hippocampal cells (Chen et al, ). To test whether the effects of NAL could be unlinked to its binding to these opioid receptors, we further tested different types of central neurons, namely, NG108‐15 neuronal cells.…”

Section: Resultsmentioning

confidence: 99%

“…The mHippoE‐14 hippocampal cell line is recognized to possess the characteristics of embryonic hippocampal neurons and useful for new therapeutics targeted to neurological disorders (Chen et al, ; Gingerich et al, ; Hsiao, Liu, Liu, & Wu, ). Earlier studies have reported the expression of μ‐ or κ‐opioid receptors in hippocampal cells (Chen et al, ). How NAL can interact with these receptors to affect the amplitude or gating of ionic currents in hippocampal neurons remains unclear, although it was previously thought to bind to opioid receptors, thus modifying ionic currents in different types of cells (Akbarali & Dewey, ; Fitting et al, ; Ross et al, ; Smith et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Effectiveness of nalbuphine, a κ‐opioid receptor agonist and μ‐opioid receptor antagonist, in the inhibition of I_Na, I_K(M), and I_K(erg) unlinked to interaction with opioid receptors

Liu

Hsiao

Wang

et al. 2019

Drug Development Research

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Nalbuphine (NAL) is recognized as a mixer with the κ‐opioid receptor agonist and the μ‐opioid receptor antagonist. However, whether this drug causes any modifications in neuronal ionic currents is unclear. The effects of NAL on ionic currents in mHippoE‐14 hippocampal neurons were investigated. In the whole‐cell current recordings, NAL suppressed the peak amplitude of voltage‐gated Na+ current (INa) with an IC50 value of 1.9 μM. It shifted the steady‐state inactivation curve of peak INa to the hyperpolarized potential, suggesting that there is the voltage dependence of NAL‐mediated inhibition of peak INa. In continued presence of NAL, subsequent application of either dynorphin A1‐13 (1 μM) or naloxone (30 μM) failed to modify its suppression of peak INa. Tefluthrin (Tef; 10 μM), a pyrethroid known to activate INa, increased peak INa with slowed current inactivation; however, further application of NAL suppressed Tef‐mediated suppression of peak INa followed by an additional slowing of current inactivation. In addition, NAL suppressed the amplitude of M‐type K+ current [IK(M)] with an IC50 value of 5.7 μM, while it slightly suppressed erg‐mediated and delayed‐rectifier K+ currents. In the inside‐out current recordings, NAL failed to modify the activity of large‐conductance Ca2+‐activated K+ channels. In differentiated NG108‐15 neuronal cells, NAL also suppressed the peak INa, and subsequent addition of Tef reversed NAL‐induced suppression of INa. Our study highlights the evidence that in addition to modulate opioid receptors, NAL has the propensity to interfere with ionic currents including INa and IK(M), thereby influencing the functional activities of central neurons.

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Heterodimerization of human orexin receptor 1 and kappa opioid receptor promotes protein kinase A/cAMP-response element binding protein signaling via a Gαs-mediated mechanism

Cited by 49 publications

References 59 publications

In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN

In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN

The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal B and β-tetrahydropyran Sal B, have anti-cocaine properties with minimal side effects

Effectiveness of nalbuphine, a κ‐opioid receptor agonist and μ‐opioid receptor antagonist, in the inhibition of I_Na, I_K(M), and I_K(erg) unlinked to interaction with opioid receptors

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Heterodimerization of human orexin receptor 1 and kappa opioid receptor promotes protein kinase A/cAMP-response element binding protein signaling via a Gαs-mediated mechanism

Cited by 49 publications

References 59 publications

In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN

In vivo actions of SCTR/AT1aR heteromer in controlling Vp expression and release via cFos/cAMP/CREB pathway in magnocellular neurons of PVN

The C-2 derivatives of salvinorin A, ethoxymethyl ether Sal B and β-tetrahydropyran Sal B, have anti-cocaine properties with minimal side effects

Effectiveness of nalbuphine, a κ‐opioid receptor agonist and μ‐opioid receptor antagonist, in the inhibition of INa, IK(M), and IK(erg) unlinked to interaction with opioid receptors

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Effectiveness of nalbuphine, a κ‐opioid receptor agonist and μ‐opioid receptor antagonist, in the inhibition of I_Na, I_K(M), and I_K(erg) unlinked to interaction with opioid receptors