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  1. Article ; Online: Design of a Tumor Binding GMCSF as Intratumoral Immunotherapy of Solid Tumors.

    Chakravarti, Aparna Raghavachar / Groer, Chad E / Gong, Huan / Yudistyra, Vivian / Forrest, Marcus Laird / Berkland, Cory J

    Molecular pharmaceutics

    2023  Volume 20, Issue 4, Page(s) 1975–1989

    Abstract: Next-generation cancer immunotherapies may utilize immunostimulants to selectively activate the host immune system against tumor cells. Checkpoint inhibitors (CPIs) like anti-PD1/PDL-1 that inhibit immunosuppression have shown unprecedented success but ... ...

    Abstract Next-generation cancer immunotherapies may utilize immunostimulants to selectively activate the host immune system against tumor cells. Checkpoint inhibitors (CPIs) like anti-PD1/PDL-1 that inhibit immunosuppression have shown unprecedented success but are only effective in the 20-30% of patients that possess an already "hot" (immunogenic) tumor. In this regard, intratumoral (IT) injection of immunostimulants is a promising approach since they can work synergistically with CPIs to overcome the resistance to immunotherapies by inducing immune stimulation in the tumor. One such immunostimulant is granulocyte macrophage-colony-stimulating factor (GMCSF) that functions by recruiting and activating antigen-presenting cells (dendritic cells) in the tumor, thereby initiating anti-tumor immune responses. However, key problems with GMCSF are lack of efficacy and the risk of systemic toxicity caused by the leakage of GMCSF from the tumor tissue. We have designed tumor-retentive versions of GMCSF that are safe yet potent immunostimulants for the local treatment of solid tumors. The engineered GMCSFs (eGMCSF) were synthesized by recombinantly fusing tumor-ECM (extracellular matrix) binding peptides to GMCSF. The eGMCSFs exhibited enhanced tumor binding and potent immunological activity in vitro and in vivo. Upon IT administration, the tumor-retentive eGMCSFs persisted in the tumor, thereby alleviating systemic toxicity, and elicited localized immune activation to effectively turn an unresponsive immunologically "cold" tumor "hot".
    MeSH term(s) Humans ; Neoplasms/therapy ; Immunotherapy ; Antigen-Presenting Cells ; Immunity ; Adjuvants, Immunologic
    Chemical Substances Adjuvants, Immunologic
    Language English
    Publishing date 2023-02-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2138405-8
    ISSN 1543-8392 ; 1543-8384
    ISSN (online) 1543-8392
    ISSN 1543-8384
    DOI 10.1021/acs.molpharmaceut.2c00897
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Glatiramer acetate enhances tumor retention and innate activation of immunostimulants.

    Pressnall, Melissa M / Huang, Aric / Groer, Chad E / Huayamares, Sebastian G / Laird Forrest, M / Berkland, Cory J

    International journal of pharmaceutics

    2021  Volume 605, Page(s) 120812

    Abstract: Cancer immunotherapy aims to stimulate immune cells to recognize and attack tumor tissue. The immunostimulatory polyanions polyI:C and CpG induce potent pro-inflammatory immune responses as TLR3 and TLR9 agonists, respectively. Clinical trials of TLR ... ...

    Abstract Cancer immunotherapy aims to stimulate immune cells to recognize and attack tumor tissue. The immunostimulatory polyanions polyI:C and CpG induce potent pro-inflammatory immune responses as TLR3 and TLR9 agonists, respectively. Clinical trials of TLR agonists, however, have been fraught with immune-related adverse events, even when injecting intratumorally in an effort to minimize systemic exposure. We identified Glatiramer Acetate (GA), a positively-charged polypeptide approved for multiple sclerosis, as a delivery agent capable of complexing with polyI:C or CpG and reducing the mobility of these actives. Small nanoparticles termed polyplexes form when mixing positively-charged GA and negatively-charged immunostimulant (polyI:C or CpG). The ratio of GA to immunostimulant directly affected the potency of TLR activation and the mobility of these actives in simulated tumor tissue. Polyplexes of GA and CpG were injected intratumorally in a tumor model of head and neck cancer (HNC) and significantly mitigated tumor growth as compared to the vehicle controls. Intratumoral injections of CpG showed the slowest tumor growth but exhibited dramatically higher systemic proinflammatory cytokine levels compared to polyplexes of GA with CpG. Sequencing of RNA from resected tumors revealed a similar pattern of upregulated proinflammatory cytokines for CpG and polyplexes, a finding supported by histological tumor staining showing similar infiltration of immune cells induced by these treatments. Intratumoral administration of polyplexes of GA with immunostimulant represents a translational approach to enhance local immune responses while mitigating systemic immune-related adverse events.
    MeSH term(s) Adjuvants, Immunologic ; Glatiramer Acetate ; Humans ; Immunotherapy ; Nanoparticles ; Neoplasms/drug therapy ; Oligodeoxyribonucleotides
    Chemical Substances Adjuvants, Immunologic ; Oligodeoxyribonucleotides ; Glatiramer Acetate (5M691HL4BO)
    Language English
    Publishing date 2021-06-16
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 428962-6
    ISSN 1873-3476 ; 0378-5173
    ISSN (online) 1873-3476
    ISSN 0378-5173
    DOI 10.1016/j.ijpharm.2021.120812
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  3. Article ; Online: Formation of platinum (II) as a six member ring for sustained polymeric delivery.

    Senadheera, Sanjeewa N / Zhang, Ti / Groer, Chad E / Forrest, M Laird

    European journal of medicinal chemistry

    2017  Volume 136, Page(s) 452–456

    Abstract: A new pH-activated polymer chelate of cisplatin was synthesized using a scalable and green aqueous technique. Synthesis of the chelate was based on formation of a 6-member ring of platinum(II) with acetyl-homo-Lysine (Ac-homo-Lys), which was accomplished ...

    Abstract A new pH-activated polymer chelate of cisplatin was synthesized using a scalable and green aqueous technique. Synthesis of the chelate was based on formation of a 6-member ring of platinum(II) with acetyl-homo-Lysine (Ac-homo-Lys), which was accomplished under completely aqueous conditions using a traceless photocleavable protection chemistry. Synthesis preceded by, first, amidation of a photocaged homo-Ac-Lys with hyaluronic acid (HA) in water using a p-hydroxyphenacyl (pHP) group as the photoremovable protecting group, followed by reaction of cisplatin (diaqua form) in water to form the reversible chelate. Platinum drug release was pH rate controlled, with more rapid release (t
    MeSH term(s) Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Chelating Agents/chemical synthesis ; Chelating Agents/chemistry ; Drug Carriers/chemical synthesis ; Drug Carriers/chemistry ; Drug Delivery Systems ; Humans ; Hydrogen-Ion Concentration ; Models, Molecular ; Molecular Structure ; Organoplatinum Compounds/chemical synthesis ; Organoplatinum Compounds/chemistry ; Polymers/chemical synthesis ; Polymers/chemistry
    Chemical Substances Antineoplastic Agents ; Chelating Agents ; Drug Carriers ; Organoplatinum Compounds ; Polymers
    Language English
    Publishing date 2017-05-06
    Publishing country France
    Document type Journal Article
    ZDB-ID 188597-2
    ISSN 1768-3254 ; 0009-4374 ; 0223-5234
    ISSN (online) 1768-3254
    ISSN 0009-4374 ; 0223-5234
    DOI 10.1016/j.ejmech.2017.05.020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 784: Show issues Location:
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  4. Article ; Online: Constructing a Biomaterial to Simulate Extracellular Drug Transport in Solid Tumors.

    Huayamares, Sebastian G / Song, Jimmy Y / Huang, Aric / Crowl, Samuel R / Groer, Chad E / Forrest, M Laird / Berkland, Cory J

    Macromolecular bioscience

    2020  Volume 20, Issue 12, Page(s) e2000251

    Abstract: Designing an in vitro model of the tumor extracellular microenvironment to screen intratumoral drugs is an active challenge. As recent clinical successes of human intratumoral therapies stimulate research on intratumoral delivery, a need for a 3D tumor ... ...

    Abstract Designing an in vitro model of the tumor extracellular microenvironment to screen intratumoral drugs is an active challenge. As recent clinical successes of human intratumoral therapies stimulate research on intratumoral delivery, a need for a 3D tumor model to screen intratumoral therapies arises. When injecting the drug formulation directly into the tumor, the biophysics affecting intratumoral retention must be considered; especially for biologic therapies, which may be dominated by extracellular transport mechanisms. Fibrotic regions in solid tumors are typically rich in collagen I fibers. Using shear rheology, head and neck tumors with higher collagen density show a higher stiffness. Similarly, the stiffness of the hyaluronic acid (HA) hydrogel models is increased by adding collagen fibers to model the bulk biomechanical properties of solid tumors. HA hydrogels are then used as intratumoral injection site simulators to model in vitro the retention of glatiramer acetate (GA) and polyethylene glycol (PEG) administered intratumorally. Both compounds are also injected in murine tumors and retention is studied ex vivo for comparison. Retention of GA in the hydrogels is significantly longer than PEG, analogous to the solid tumors, suggesting the utility of HA hydrogels with collagen I fibers for screening extracellular drug transport after intratumoral administration.
    MeSH term(s) Animals ; Biocompatible Materials/metabolism ; Biocompatible Materials/pharmacology ; Cell Line, Tumor ; Drug Carriers/chemistry ; Drug Carriers/pharmacology ; Drug Compounding ; Drug Delivery Systems ; Glatiramer Acetate/chemistry ; Head and Neck Neoplasms/drug therapy ; Head and Neck Neoplasms/metabolism ; Humans ; Hyaluronic Acid/chemistry ; Hydrogels/chemistry ; Hydrogels/pharmacology ; Mice ; Polyethylene Glycols/pharmacology ; Xenograft Model Antitumor Assays
    Chemical Substances Biocompatible Materials ; Drug Carriers ; Hydrogels ; Polyethylene Glycols (3WJQ0SDW1A) ; Glatiramer Acetate (5M691HL4BO) ; Hyaluronic Acid (9004-61-9)
    Language English
    Publishing date 2020-09-13
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2039130-4
    ISSN 1616-5195 ; 1616-5187
    ISSN (online) 1616-5195
    ISSN 1616-5187
    DOI 10.1002/mabi.202000251
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  5. Article: Studies toward the Development of Antiproliferative Neoclerodanes from Salvinorin A

    Vasiljevik, Tamara / Groer Chad E / Lehner Kurt / Navarro Hernan / Prisinzano Thomas E

    Journal of natural products. 2014 Aug. 22, v. 77, no. 8

    2014  

    Abstract: The success rate for central nervous system (CNS) drug candidates in the clinic is relatively low compared to the industry average across other therapeutic areas. Penetration through the blood–brain barrier (BBB) to reach the therapeutic target is a ... ...

    Abstract The success rate for central nervous system (CNS) drug candidates in the clinic is relatively low compared to the industry average across other therapeutic areas. Penetration through the blood–brain barrier (BBB) to reach the therapeutic target is a major obstacle in development. The rapid CNS penetration of salvinorin A has suggested that the neoclerodane nucleus offers an excellent scaffold for developing antiproliferative compounds that enter the CNS. The Liebeskind–Srogl reaction was used as the main carbon–carbon bond-forming step toward the synthesis of quinone-containing salvinorin A analogues. Quinone-containing salvinorin A analogues were shown to have antiproliferative activity against the MCF7 breast cancer cell line, but show no significant activity at the κ-opioid receptors. In an in vitro model of BBB penetration, quinone-containing salvinorin A analogues were shown to passively diffuse across the cell monolayer. The analogues, however, are substrates of P-glycoprotein, and thus further modification of the molecules is needed to reduce the affinity for the efflux transporter.
    Keywords P-glycoproteins ; anticarcinogenic activity ; blood-brain barrier ; breast neoplasms ; central nervous system ; drugs ; models ; receptors
    Language English
    Dates of publication 2014-0822
    Size p. 1817-1824.
    Publishing place American Chemical Society and American Society of Pharmacognosy
    Document type Article
    ZDB-ID 304325-3
    ISSN 1520-6025 ; 0163-3864
    ISSN (online) 1520-6025
    ISSN 0163-3864
    DOI 10.1021%2Fnp5002048
    Database NAL-Catalogue (AGRICOLA)

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  6. Article ; Online: Studies toward the Development of Antiproliferative Neoclerodanes from Salvinorin A.

    Vasiljevik, Tamara / Groer, Chad E / Lehner, Kurt / Navarro, Hernan / Prisinzano, Thomas E

    Journal of natural products

    2014  Volume 77, Issue 8, Page(s) 1817–1824

    Abstract: The success rate for central nervous system (CNS) drug candidates in the clinic is relatively low compared to the industry average across other therapeutic areas. Penetration through the blood-brain barrier (BBB) to reach the therapeutic target is a ... ...

    Abstract The success rate for central nervous system (CNS) drug candidates in the clinic is relatively low compared to the industry average across other therapeutic areas. Penetration through the blood-brain barrier (BBB) to reach the therapeutic target is a major obstacle in development. The rapid CNS penetration of salvinorin A has suggested that the neoclerodane nucleus offers an excellent scaffold for developing antiproliferative compounds that enter the CNS. The Liebeskind-Srogl reaction was used as the main carbon-carbon bond-forming step toward the synthesis of quinone-containing salvinorin A analogues. Quinone-containing salvinorin A analogues were shown to have antiproliferative activity against the MCF7 breast cancer cell line, but show no significant activity at the κ-opioid receptors. In an in vitro model of BBB penetration, quinone-containing salvinorin A analogues were shown to passively diffuse across the cell monolayer. The analogues, however, are substrates of P-glycoprotein, and thus further modification of the molecules is needed to reduce the affinity for the efflux transporter.
    MeSH term(s) ATP Binding Cassette Transporter, Subfamily B/metabolism ; ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism ; Blood-Brain Barrier/metabolism ; Cell Proliferation/drug effects ; Central Nervous System Agents ; Diterpenes, Clerodane/chemistry ; Diterpenes, Clerodane/pharmacology ; Drug Screening Assays, Antitumor ; Female ; Humans ; Molecular Structure ; Receptors, Opioid, kappa/metabolism ; Salvia/chemistry
    Chemical Substances ATP Binding Cassette Transporter, Subfamily B ; ATP Binding Cassette Transporter, Subfamily B, Member 1 ; Central Nervous System Agents ; Diterpenes, Clerodane ; Receptors, Opioid, kappa ; salvinorin A (T56W91NG6J)
    Language English
    Publishing date 2014-07-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 304325-3
    ISSN 1520-6025 ; 0163-3864
    ISSN (online) 1520-6025
    ISSN 0163-3864
    DOI 10.1021/np5002048
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Agonist-directed interactions with specific beta-arrestins determine mu-opioid receptor trafficking, ubiquitination, and dephosphorylation.

    Groer, Chad E / Schmid, Cullen L / Jaeger, Alex M / Bohn, Laura M

    The Journal of biological chemistry

    2011  Volume 286, Issue 36, Page(s) 31731–31741

    Abstract: Morphine and other opiates mediate their effects through activation of the μ-opioid receptor (MOR), and regulation of the MOR has been shown to critically affect receptor responsiveness. Activation of the MOR results in receptor phosphorylation, β- ... ...

    Abstract Morphine and other opiates mediate their effects through activation of the μ-opioid receptor (MOR), and regulation of the MOR has been shown to critically affect receptor responsiveness. Activation of the MOR results in receptor phosphorylation, β-arrestin recruitment, and internalization. This classical regulatory process can differ, depending on the ligand occupying the receptor. There are two forms of β-arrestin, β-arrestin1 and β-arrestin2 (also known as arrestin2 and arrestin3, respectively); however, most studies have focused on the consequences of recruiting β-arrestin2 specifically. In this study, we examine the different contributions of β-arrestin1- and β-arrestin2-mediated regulation of the MOR by comparing MOR agonists in cells that lack expression of individual or both β-arrestins. Here we show that morphine only recruits β-arrestin2, whereas the MOR-selective enkephalin [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]enkephalin (DAMGO), recruits either β-arrestin. We show that β-arrestins are required for receptor internalization and that only β-arrestin2 can rescue morphine-induced MOR internalization, whereas either β-arrestin can rescue DAMGO-induced MOR internalization. DAMGO activation of the receptor promotes MOR ubiquitination over time. Interestingly, β-arrestin1 proves to be critical for MOR ubiquitination as modification does not occur in the absence of β-arrestin1 nor when morphine occupies the receptor. Moreover, the selective interactions between the MOR and β-arrestin1 facilitate receptor dephosphorylation, which may play a role in the resensitization of the MOR and thereby contribute to overall development of opioid tolerance.
    MeSH term(s) Analgesics, Opioid ; Animals ; Arrestins/agonists ; Arrestins/metabolism ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology ; Enkephalins ; Mice ; Phosphorylation ; Protein Transport ; Receptors, Opioid, mu/metabolism ; Ubiquitination ; beta-Arrestins
    Chemical Substances Analgesics, Opioid ; Arrestins ; Enkephalins ; Oprm protein, mouse ; Receptors, Opioid, mu ; beta-Arrestins ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)- (100929-53-1)
    Language English
    Publishing date 2011-07-14
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M111.248310
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Functional selectivity at the μ-opioid receptor: implications for understanding opioid analgesia and tolerance.

    Raehal, Kirsten M / Schmid, Cullen L / Groer, Chad E / Bohn, Laura M

    Pharmacological reviews

    2011  Volume 63, Issue 4, Page(s) 1001–1019

    Abstract: Opioids are the most effective analgesic drugs for the management of moderate or severe pain, yet their clinical use is often limited because of the onset of adverse side effects. Drugs in this class produce most of their physiological effects through ... ...

    Abstract Opioids are the most effective analgesic drugs for the management of moderate or severe pain, yet their clinical use is often limited because of the onset of adverse side effects. Drugs in this class produce most of their physiological effects through activation of the μ opioid receptor; however, an increasing number of studies demonstrate that different opioids, while presumably acting at this single receptor, can activate distinct downstream responses, a phenomenon termed functional selectivity. Functional selectivity of receptor-mediated events can manifest as a function of the drug used, the cellular or neuronal environment examined, or the signaling or behavioral measure recorded. This review summarizes both in vitro and in vivo work demonstrating functional selectivity at the μ opioid receptor in terms of G protein coupling, receptor phosphorylation, interactions with β-arrestins, receptor desensitization, internalization and signaling, and details on how these differences may relate to the progression of analgesic tolerance after their extended use.
    MeSH term(s) Analgesics/pharmacology ; Analgesics/therapeutic use ; Analgesics, Opioid/pharmacology ; Analgesics, Opioid/therapeutic use ; Drug Tolerance ; GTP-Binding Protein Regulators/drug effects ; GTP-Binding Protein Regulators/physiology ; Humans ; Pain/drug therapy ; Pain/physiopathology ; Receptors, Opioid, mu/physiology
    Chemical Substances Analgesics ; Analgesics, Opioid ; GTP-Binding Protein Regulators ; Receptors, Opioid, mu
    Language English
    Publishing date 2011-08-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 209898-2
    ISSN 1521-0081 ; 0031-6997
    ISSN (online) 1521-0081
    ISSN 0031-6997
    DOI 10.1124/pr.111.004598
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Synthesis and κ-opioid receptor activity of furan-substituted salvinorin A analogues.

    Riley, Andrew P / Groer, Chad E / Young, David / Ewald, Amy W / Kivell, Bronwyn M / Prisinzano, Thomas E

    Journal of medicinal chemistry

    2014  Volume 57, Issue 24, Page(s) 10464–10475

    Abstract: The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent κ-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic ... ...

    Abstract The neoclerodane diterpene salvinorin A, found in the leaves of Salvia divinorum, is a potent κ-opioid receptor agonist, making it an attractive scaffold for development into a treatment for substance abuse. Although several successful semisynthetic studies have been performed to elucidate structure-activity relationships, the lack of analogues with substitutions to the furan ring of salvinorin A has prevented a thorough understanding of its role in binding to the κ-opioid receptor. Herein we report the synthesis of several salvinorin A derivatives with modified furan rings. Evaluation of these compounds in a functional assay indicated that sterically less demanding substitutions are preferred, suggesting the furan ring is bound in a congested portion of the binding pocket. The most potent of the analogues successfully reduced drug-seeking behavior in an animal model of drug-relapse without producing the sedation observed with other κ-opioid agonists.
    MeSH term(s) Animals ; CHO Cells ; Cricetulus ; Diterpenes, Clerodane/chemistry ; Diterpenes, Clerodane/pharmacology ; Furans/chemistry ; Hallucinogens/chemistry ; Hallucinogens/pharmacology ; Male ; Models, Molecular ; Molecular Structure ; Motor Activity/drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, kappa/agonists ; Salvia/chemistry ; Structure-Activity Relationship
    Chemical Substances Diterpenes, Clerodane ; Furans ; Hallucinogens ; Receptors, Opioid, kappa ; salvinorin A (T56W91NG6J) ; furan (UC0XV6A8N9)
    Language English
    Publishing date 2014-12-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm501521d
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Functional selectivity of 6'-guanidinonaltrindole (6'-GNTI) at κ-opioid receptors in striatal neurons.

    Schmid, Cullen L / Streicher, John M / Groer, Chad E / Munro, Thomas A / Zhou, Lei / Bohn, Laura M

    The Journal of biological chemistry

    2013  Volume 288, Issue 31, Page(s) 22387–22398

    Abstract: There is considerable evidence to suggest that drug actions at the κ-opioid receptor (KOR) may represent a means to control pain perception and modulate reward thresholds. As a G protein-coupled receptor (GPCR), the activation of KOR promotes Gαi/o ... ...

    Abstract There is considerable evidence to suggest that drug actions at the κ-opioid receptor (KOR) may represent a means to control pain perception and modulate reward thresholds. As a G protein-coupled receptor (GPCR), the activation of KOR promotes Gαi/o protein coupling and the recruitment of β-arrestins. It has become increasingly evident that GPCRs can transduce signals that originate independently via G protein pathways and β-arrestin pathways; the ligand-dependent bifurcation of such signaling is referred to as "functional selectivity" or "signaling bias." Recently, a KOR agonist, 6'-guanidinonaltrindole (6'-GNTI), was shown to display bias toward the activation of G protein-mediated signaling over β-arrestin2 recruitment. Therefore, we investigated whether such ligand bias was preserved in striatal neurons. Although the reference KOR agonist U69,593 induces the phosphorylation of ERK1/2 and Akt, 6'-GNTI only activates the Akt pathway in striatal neurons. Using pharmacological tools and β-arrestin2 knock-out mice, we show that KOR-mediated ERK1/2 phosphorylation in striatal neurons requires β-arrestin2, whereas Akt activation depends upon G protein signaling. These findings reveal a point of KOR signal bifurcation that can be observed in an endogenous neuronal setting and may prove to be an important indicator when developing biased agonists at the KOR.
    MeSH term(s) Animals ; CHO Cells ; Corpus Striatum/cytology ; Corpus Striatum/drug effects ; Corpus Striatum/metabolism ; Cricetinae ; Cricetulus ; Guanidines/pharmacology ; MAP Kinase Signaling System ; Male ; Mice ; Naltrexone/analogs & derivatives ; Naltrexone/pharmacology ; Neurons/drug effects ; Neurons/metabolism ; Phosphorylation ; Receptors, Opioid, kappa/drug effects
    Chemical Substances 6'-guanidinonaltrindole ; Guanidines ; Receptors, Opioid, kappa ; Naltrexone (5S6W795CQM)
    Language English
    Publishing date 2013-06-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M113.476234
    Database MEDical Literature Analysis and Retrieval System OnLINE

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