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Plant-Derived Cyclotides Modulate κ-Opioid Receptor Signaling.

ABSTRACT: Cyclotides are plant-derived disulfide-rich peptides comprising a cyclic cystine knot, which confers remarkable stability against thermal, proteolytic, and chemical degradation. They represent an emerging class of G protein-coupled receptor (GPCR) ligands. In this study, utilizing a screening approach of plant extracts and pharmacological analysis we identified cyclotides from Carapichea ipecacuanha to be ligands of the κ-opioid receptor (KOR), an attractive target for developing analgesics with reduced side effects and therapeutics for multiple sclerosis (MS). This prompted us to verify whether [T20K]kalata B1, a cyclotide in clinical development for the treatment of MS, is able to modulate KOR signaling. T20K bound to and fully activated KOR in the low μM range. We then explored the ability of T20K to allosterically modulate KOR. Co-incubation of T20K with KOR ligands resulted in positive allosteric modulation in functional cAMP assays by altering either the efficacy of dynorphin A_1-13 or the potency and efficacy of U50,488 (a selective KOR agonist), respectively. In addition, T20K increased the basal response upon cotreatment with U50,488. In the bioluminescence resonance energy transfer assay T20K negatively modulated the efficacy of U50,488. This study identifies cyclotides capable of modulating KOR and highlights the potential of plant-derived peptides as an opportunity to develop cyclotide-based KOR modulators.

SUBMITTER: Muratspahic E

PROVIDER: S-EPMC8406418 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Plant-Derived Cyclotides Modulate κ-Opioid Receptor Signaling.

Muratspahić Edin E Tomašević Nataša N Nasrollahi-Shirazi Shahrooz S Gattringer Jasmin J Emser Fabiola Susanna FS Freissmuth Michael M Gruber Christian W CW

Journal of natural products 20210726 8

Cyclotides are plant-derived disulfide-rich peptides comprising a cyclic cystine knot, which confers remarkable stability against thermal, proteolytic, and chemical degradation. They represent an emerging class of G protein-coupled receptor (GPCR) ligands. In this study, utilizing a screening approach of plant extracts and pharmacological analysis we identified cyclotides from <i>Carapichea ipecacuanha</i> to be ligands of the κ-opioid receptor (KOR), an attractive target for developing analgesi ...[more]

PMID: 34308635

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Project description:Kappa opioid receptor (KOR) agonists are potentially useful as analgesic and anti-pruritic agents, for prevention and treatment of substance use disorders, and for treatment of demyelinating diseases. However, side effects of KOR agonists, including psychotomimesis, dysphoria, and sedation, have caused early termination of clinical trials. Understanding the signaling mechanisms underlying the beneficial therapeutic effects and the adverse side effects may help in the development of KOR agonist compounds. In this review, we summarize the current knowledge in this regard in five sections. First, studies conducted on mutant mouse lines (GRK3-/-, p38alpha MAPK-/-, β-arrestin2-/-, phosphorylation-deficient KOR) are summarized. In addition, the abilities of four distinct KOR agonists, which have analgesic and anti-pruritic effects with different side effect profiles, to cause KOR phosphorylation are discussed. Second, investigations on the KOR agonist nalfurafine, both in vitro and in vivo are reviewed. Nalfurafine was the first KOR full agonist approved for clinical use and in the therapeutic dose range it did not produce significant side effects associated with typical KOR agonists. Third, large-scale high-throughput phosphoproteomic studies without a priori hypotheses are described. These studies have revealed that KOR-mediated side effects are associated with many signaling pathways. Fourth, several novel G protein-biased KOR agonists that have been characterized for in vitro biochemical properties and agonist biases and in vivo behavior effects are described. Lastly, possible mechanisms underlying KOR-mediated CPA, hypolocomotion and motor incoordination are discussed. Overall, it is agreed upon that the analgesic and anti-pruritic effects of KOR agonists are mediated via G protein signaling. However, there is no consensus on the mechanisms underlying their side effects. GRK3, p38 MAPK, β-arrestin2, mTOR pathway, CB1 cannabinoid receptor and protein kinase C have been implicated in one side effect or another. For drug discovery, after initial in vitro characterization, in vivo pharmacological characterizations in various behavior tests are still the most crucial steps and dose separation between beneficial therapeutic effects and adverse side effects are the critical determinant for the compounds to be moved forward for clinical development.

Project description:The lateral habenula (LHb) is an epithalamic brain region associated with value-based decision making and stress evasion through its modulation of dopamine (DA)-mediated reward circuitry. Specifically, increased activity of the LHb is associated with drug addiction, schizophrenia and stress-related disorders such as depression, anxiety and posttraumatic stress disorder. Dynorphin (Dyn)/Kappa opioid receptor (KOR) signaling is a mediator of stress response in reward circuitry. Previously, we have shown that maternal deprivation (MD), a severe early life stress, increases LHb spontaneous neuronal activity and intrinsic excitability while blunting the response of LHb neurons to extrahypothalamic corticotropin-releasing factor (CRF) signaling, another stress mediator. CRF pathways also interact with Dyn/KOR signaling. Surprisingly, there has been little study of direct KOR regulation of the LHb despite its distinct role in stress, reward and aversion processing. To test the functional role of Dyn/KOR signaling in the LHb, we utilized ex-vivo electrophysiology combined with pharmacological tools in rat LHb slices. We show that activation of KORs by a KOR agonist (U50,488) exerted differential effects on the excitability of two distinct sub-populations of LHb neurons that differed in their expression of hyperpolarization-activated cation currents (HCN, Ih). Specifically, KOR stimulation increased neuronal excitability in LHb neurons with large Ih currents (Ih+) while decreasing neuronal excitability in small/negative Ih (Ih-) neurons. We found that an intact fast-synaptic transmission was required for the effects of U50,488 on the excitability of both Ih- and Ih+ LHb neuronal subpopulations. While AMPAR-, GABAAR-, or NMDAR-mediated synaptic transmission alone was sufficient to mediate the effects of U50,488 on excitability of Ih- neurons, either GABAAR- or NMDAR-mediated synaptic transmission could mediate these effects in Ih+ neurons. Consistently, KOR activation also altered both glutamatergic and GABAergic synaptic transmission where stimulation of presynaptic KORs uniformly suppressed glutamate release onto LHb neurons while primarily decreased or in some cases increased GABA release. We also found that MD significantly increased immunolabeled Dyn (the endogenous KOR agonist) labeling in neuronal fibers in LHb while significantly decreasing mRNA levels of KORs in LHb tissues compared to those from non-maternally deprived (non-MD) control rats. Moreover, the U50,488-mediated increase in LHb neuronal firing observed in non-MD rats was absent following MD. Altogether, this is the first demonstration of the existence of functional Dyn/KOR signaling in the LHb that can be modulated in response to severe early life stressors such as MD.

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Plant-Derived Cyclotides Modulate κ-Opioid Receptor Signaling.

Publications

Plant-Derived Cyclotides Modulate κ-Opioid Receptor Signaling.

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