Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABA<sub>B</sub> receptors and reduce neuroexcitability

Bony, Anuja R.; McArthur, Jeffrey R.; Finol‐Urdaneta, Rocio K.; Adams, David J.

doi:10.1111/bph.15690

Cited by 7 publications

(14 citation statements)

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“…Several studies have indicated that certain α-conopeptides act as agonists of the GABA B receptor resulting in analgesic effects [ 42 , 43 , 44 , 45 ]. This has led to questions regarding the role and necessity of α9-containing nAChRs in mediating α-conopeptide analgesia.…”

Section: Discussionmentioning

confidence: 99%

RgIA4 Prevention of Acute Oxaliplatin-Induced Cold Allodynia Requires α9-Containing Nicotinic Acetylcholine Receptors and CD3+ T-Cells

Huynh

Christensen

McIntosh

2022

Cells

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Chemotherapy-induced neuropathic pain is a debilitating and dose-limiting side effect. Oxaliplatin is a third-generation platinum and antineoplastic compound that is commonly used to treat colorectal cancer and commonly yields neuropathic side effects. Available drugs such as duloxetine provide only modest benefits against oxaliplatin-induced neuropathy. A particularly disruptive symptom of oxaliplatin is painful cold sensitivity, known as cold allodynia. Previous studies of the Conus regius peptide, RgIA, and its analogs have demonstrated relief from oxaliplatin-induced cold allodynia, yielding improvement that persists even after treatment cessation. Moreover, underlying inflammatory and neuronal protection were shown at the cellular level in chronic constriction nerve injury models, consistent with disease-modifying effects. Despite these promising preclinical outcomes, the underlying molecular mechanism of action of RgIA4 remains an area of active investigation. This study aimed to determine the necessity of the α9 nAChR subunit and potential T-cell mechanisms in RgIA4 efficacy against acute oxaliplatin-induced cold allodynia. A single dose of oxaliplatin (10 mg/kg) was utilized followed by four daily doses of RgIA4. Subcutaneous administration of RgIA4 (40 µg/kg) prevented cold allodynia in wildtype mice but not in mice lacking the α9 nAChR-encoding gene, chrna9. RgIA4 also failed to reverse allodynia in mice depleted of CD3+ T-cells. In wildtype mice treated with oxaliplatin, quantitated circulating T-cells remained unaffected by RgIA4. Together, these results show that RgIA4 requires both chrna9 and CD3+ T-cells to exert its protective effects against acute cold-allodynia produced by oxaliplatin.

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Section: Discussionmentioning

confidence: 99%

RgIA4 Prevention of Acute Oxaliplatin-Induced Cold Allodynia Requires α9-Containing Nicotinic Acetylcholine Receptors and CD3+ T-Cells

Huynh

Christensen

McIntosh

2022

Cells

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“…The role of cholinergic and GABA B -ergic systems in the analgesic action of these conopeptides is still being discussed and is reflected in numerous experimental studies and reviews (see, for example, [ 184 , 193 , 194 ]). Perhaps the analgesic mechanism is even more complex, since the first data on the modulation of G protein-coupled inwardly rectifying potassium (GIRK) channels by these conotoxins via the activation of GABA B receptors have appeared [ 195 ]. Meanwhile, over the past decade, new data have appeared on analgesic activity in various animal pain models for other conopeptides, in particular, for all three isomers of αO-conotoxin GeXIVA [ 100 , 196 , 197 ], αL-conotoxin lt14a [ 198 , 199 ], α-conotoxins AuIB, MII [ 200 ], BuIA and its analogues [ 201 ], and LvIA [ 202 ].…”

Section: Marine Origin Peptides Targeting Nachrsmentioning

confidence: 99%

Marine Origin Ligands of Nicotinic Receptors: Low Molecular Compounds, Peptides and Proteins for Fundamental Research and Practical Applications

et al. 2022

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The purpose of our review is to briefly show what different compounds of marine origin, from low molecular weight ones to peptides and proteins, offer for understanding the structure and mechanism of action of nicotinic acetylcholine receptors (nAChRs) and for finding novel drugs to combat the diseases where nAChRs may be involved. The importance of the mentioned classes of ligands has changed with time; a protein from the marine snake venom was the first excellent tool to characterize the muscle-type nAChRs from the electric ray, while at present, muscle and α7 receptors are labeled with the radioactive or fluorescent derivatives prepared from α-bungarotoxin isolated from the many-banded krait. The most sophisticated instruments to distinguish muscle from neuronal nAChRs, and especially distinct subtypes within the latter, are α-conotoxins. Such information is crucial for fundamental studies on the nAChR revealing the properties of their orthosteric and allosteric binding sites and mechanisms of the channel opening and closure. Similar data are provided by low-molecular weight compounds of marine origin, but here the main purpose is drug design. In our review we tried to show what has been obtained in the last decade when the listed classes of compounds were used in the nAChR research, applying computer modeling, synthetic analogues and receptor mutants, X-ray and electron-microscopy analyses of complexes with the nAChRs, and their models which are acetylcholine-binding proteins and heterologously-expressed ligand-binding domains.

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“…Docking calculations were also performed on the negative control peptides, α-conotoxin ImI, and the RgIA analogue, RgIA4 (Romero et al, 2017), both of which are inactive at GABA B R (Callaghan et al, 2008;Romero et al, 2017;Bony et al, 2022). Both peptides are predicted to form far fewer contacts with subunit B1, and exhibit stronger preferences for binding to B2, compared to the active conotoxins Vc1.1, RgIA, and PeIA.…”

Section: Negative Control Peptides Imi and Rgia4mentioning

confidence: 99%

Analgesic α-Conotoxin Binding Site on the Human GABA_B Receptor

et al. 2022

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The analgesic α-conotoxins Vc1.1, RgIA, and PeIA attenuate nociceptive transmission via activation of G protein-coupled GABA B receptors (GABA B R) to modulate N-type calcium channels in primary afferent neurons and recombinantly co-expressed human GABA B R and Cav2.2 channels in HEK293T cells. Here, we investigated the effects of analgesic αconotoxins following the mutation of amino acid residues in the Venus Flytrap (VFT) domains of the GABA B R subunits predicted through computational peptide docking and molecular dynamics simulations. Our docking calculations predicted that all three of the αconotoxins form close contacts with VFT residues in both B1 and B2 subunits, comprising a novel GABA B R ligand-binding site. The effects of baclofen and α-conotoxins on the peak Ba 2+ current (I Ba ) amplitude were investigated on wild-type and 15 GABA B R mutants individually co-expressed with human Cav2.2 channels. Mutations at the interface of the VFT domains of both GABA B R subunits attenuated baclofen-sensitive I Ba inhibition by the analgesic α-conotoxins. In contrast, mutations located outside the putative peptide-binding site (D380A and R98A) did not. The key GABA B R residues involved in interactions with the α-conotoxins are K168 and R207 on the B2 subunit and S130, S153, R162, E200, F227, and E253 on the B1 subunit. The double mutant, S130A+S153A, abolished inhibition by both baclofen and the α-conotoxins. Depolarization-activated I Ba mediated by both wild-type and all GABA B R mutants were inhibited by the selective GABA B R antagonist CGP 55845. This study identifies specific residues of GABA B R involved in the binding of the analgesic αconotoxins to the VFT domains of the GABA B R.

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Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABA_B receptors and reduce neuroexcitability

Cited by 7 publications

References 92 publications

RgIA4 Prevention of Acute Oxaliplatin-Induced Cold Allodynia Requires α9-Containing Nicotinic Acetylcholine Receptors and CD3+ T-Cells

RgIA4 Prevention of Acute Oxaliplatin-Induced Cold Allodynia Requires α9-Containing Nicotinic Acetylcholine Receptors and CD3+ T-Cells

Marine Origin Ligands of Nicotinic Receptors: Low Molecular Compounds, Peptides and Proteins for Fundamental Research and Practical Applications

Analgesic α-Conotoxin Binding Site on the Human GABA_B Receptor

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Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABAB receptors and reduce neuroexcitability

Cited by 7 publications

References 92 publications

RgIA4 Prevention of Acute Oxaliplatin-Induced Cold Allodynia Requires α9-Containing Nicotinic Acetylcholine Receptors and CD3+ T-Cells

RgIA4 Prevention of Acute Oxaliplatin-Induced Cold Allodynia Requires α9-Containing Nicotinic Acetylcholine Receptors and CD3+ T-Cells

Marine Origin Ligands of Nicotinic Receptors: Low Molecular Compounds, Peptides and Proteins for Fundamental Research and Practical Applications

Analgesic α-Conotoxin Binding Site on the Human GABAB Receptor

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Product

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Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABA_B receptors and reduce neuroexcitability

Analgesic α-Conotoxin Binding Site on the Human GABA_B Receptor