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Articles, Cellular/Molecular

Analgesic α-Conotoxins Vc1.1 and Rg1A Inhibit N-Type Calcium Channels in Rat Sensory Neurons via GABAB Receptor Activation

Brid Callaghan, Alison Haythornthwaite, Géza Berecki, Richard J. Clark, David J. Craik and David J. Adams
Journal of Neuroscience 22 October 2008, 28 (43) 10943-10951; https://doi.org/10.1523/JNEUROSCI.3594-08.2008
Brid Callaghan
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Alison Haythornthwaite
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Géza Berecki
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Richard J. Clark
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David J. Craik
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David J. Adams
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  • Figure 1.
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    Figure 1.

    α-Conotoxin Vc1.1 inhibits HVA calcium channels in rat DRG neurons. A, Superimposed traces of depolarization-activated whole-cell calcium channel currents recorded using 2 mm Ba2+ as the charge carrier, elicited by a voltage step from a holding potential of −50 to 0 mV in the absence (a) and presence (b) of 100 nm Vc1.1. B, Corresponding time course of inhibition of peak Ba2+ current amplitude by 100 nm Vc1.1. Application of Vc1.1 is indicated by the bar. C, Plot of the I–V relationship for peak Ba2+ currents in the presence (●) and absence (○) of Vc1.1 (≤ 100 nm) (n = 16). D, Concentration–response curve for inhibition of calcium channel currents in DRG neurons by Vc1.1. Data points represent mean ± SEM of normalized peak current amplitude (n = 8–25 cells per data point). Maximum inhibition was 42 ± 3% with an IC50 of 1.7 nm.

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    Figure 2.

    Vc1.1 inhibition of HVA calcium channel currents is use dependent. A, Representative time course of peak Ba2+ current amplitude recorded using a 15 ms step depolarization from a holding potential of −80 mV to a test potential of −10 mV at a frequency of either 0.05 or 0.1 Hz, as indicated, in the absence and presence of 100 nm Vc1.1. B, Bar graph of the relative inhibition of HVA calcium channel currents by 100 nm Vc1.1 during a 15 ms depolarization at a frequency of either 0.05 Hz (n = 24) or 0.1 Hz (n = 7 responsive cells of 7 tested), and a pulse duration of 150 ms and frequency of either 0.05 Hz (n = 36 responsive cells of 50 tested) or 0.1 Hz (n = 9 responsive cells of 12 tested).***p < 0.001 unpaired t test. C, Superimposed traces of depolarization-activated whole-cell Ca2+ channel currents recorded using 2 mm Ca2+as the charge carrier, elicited by a voltage step from a holding potential of −80 to 0 mV in the absence (a) and presence (b) of 100 nm Vc1.1.

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    Figure 3.

    Vc1.1 post-translationally modified analogs and other α-conotoxins are without effect on HVA calcium channel currents. A, Representative time course of peak Ba2+ current amplitude in the presence of 100 nm RgIA. The holding potential was −80 mV and the test potential −10 mV. B, Representative time course of peak Ba2+ current amplitude in the presence of 1 μm vc1a. C, Bar graph of relative inhibition of HVA calcium channel currents by α-conotoxins RgIA, ImI, [A10L]PnIA, MII, BuIA, alkylated Vc1.1, Vc1.1, and analogs. Vc1.1 (1 μm) inhibited peak Ba2+ current amplitude in 25 of 30 cells tested. ***p = 0.0001 compared with control cells. Rg1A (100 nm) inhibited peak Ba2+ current amplitude in 11 of 14 cells tested. **p = 0.0016 compared with control cells. Numbers in parentheses reflect the number of cells.

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    Figure 4.

    Vc1.1 inhibits N-type calcium channels in rat DRG neurons. A, Superimposed traces of depolarization-activated whole-cell Ba2+ currents under control conditions (a), in the presence of 200 nm ω-conotoxin CVID (b), and in the presence of CVID and 1 μm Vc1.1 (c). B, Representative time course of peak Ba2+ current amplitude in the presence of the selective N-type Ca2+ channel inhibitor ω-conotoxin CVID followed by application of Vc1.1. The letters a–c indicate the time points at which the superimposed currents were obtained. C, Bar graph of relative inhibition of HVA calcium channel currents by 200 nm CVID alone, after application of 1 μm Vc1.1 in the presence of CVID, in the presence of Vc1.1 alone, and after application of CVID in the presence Vc1.1. Numbers in parentheses reflect the number of cells.

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    Figure 5.

    Vc1.1 does not inhibit Ba2+ currents through recombinant N- and P/Q-type channels expressed in Xenopus oocytes. A, Superimposed current traces from an oocyte expressing Cav2.2 α1B-d/β3/α2δ1 (N-type) calcium channels under control conditions (a) and in the presence of 1 μm Vc1.1 (b). B, Superimposed currents from an oocyte expressing Cav2.1 α1E/β3/α2δ1 (P/Q-type) calcium channels in the absence (control) (a) and presence (b) of 1 μm Vc1.1. C, Bar graph of relative current amplitude obtained for expressed N- and P/Q-type calcium channels in the presence of 1 μm Vc1.1. Numbers in parentheses reflect the number of cells.

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    Figure 6.

    Vc1.1 inhibition of N-type calcium channel currents is mediated by G-protein-coupled receptor and tyrosine kinase activation. A(i), Superimposed traces in the absence (a) and presence (b) of 1 μm Vc1.1 in cells incubated overnight in PTX (3 μg/ml). Cells were recorded under continual perfusion of PTX (200 ng/ml). (ii), Corresponding time course. B(i), Superimposed traces in the absence (a) and presence (b) of Vc1.1 (1 μm) in cells recorded with pp60c-src peptide (521-533) inhibitory peptide (100 μm) included in the recording pipette. (ii), Corresponding time course. C, Bar graph of relative inhibition of HVA calcium channel currents by Vc1.1 (1 μm) in regular recording solution (GTP), when a prepulse to +80 mV (+PP) was applied 10 ms before the test pulse, when GTP was replaced with GDPβS, after overnight incubation in PTX, or when pp60c-src inhibitory peptide was included in the pipette recording solution. ***p = 0.0001 compared with control. Numbers in parentheses reflect the number of cells.

  • Figure 7.
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    Figure 7.

    GABAB receptor activation mediates Vc1.1 inhibition of N-type calcium channel currents in rat DRG neurons. A(i), Superimposed traces of depolarization-activated whole-cell Ba2+ currents in the presence of the GABAB inhibitor phaclofen (50 μm) followed by application of 100 nm Vc1.1. (ii), Corresponding time course. Numbers on the plot indicate which points were used for sample traces in A(i). B(i), Superimposed traces of depolarization-activated whole-cell Ba2+ currents in the presence of another GABAB inhibitor CGP55845 (1 μm) (a), in the presence of CGP55845 and Vc1.1 (100 nm) (b), and in the presence of Vc1.1 alone (100 nm) (c). (ii), Corresponding time course. Numbers on the plot indicate which points were used for sample traces in B(i). C(i), Superimposed traces of depolarization-activated whole-cell Ba2+ currents in the absence (a), in the presence of the GABAB agonist baclofen (30 μm) (b), and in the presence of 100 nm Vc1.1 (c). (ii), Corresponding time course. Numbers on the plot indicate which points were used for sample traces in C(i).

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    Table 1.

    Receptor antagonists tested for reversal of the inhibition of N-type calcium channel currents by α-conotoxin Vc1.1

    Antagonist (concentration)Target receptorAntagonist of Vc1.1 inhibitionPercentage inhibition of IBa by Vc1.1 (n)
    Mecamylamine (3 μm)nAChR−29.2 ± 8.6 (3)
    ACh (100 μm)nAChR−28.4 ± 4.5 (7)
    Atropine (1 μm)mAChR−27.2 ± 10.4 (4)
    Prazosin (10 μm)α1-Adrenergic−41.3 ± 4.8 (3)
    Yohimbine (10 μm)α2-Adrenergic−35.8 ± 11.5 (3)
    Naloxone (10 μm)μ-Opioid−50.1 ± 12.4 (3)
    Bicuculline (30 μm)GABAA−32.9 ± 7.0 (10)
    Phaclofen (50 μm)GABAB+4.6 ± 4.4 (9)
    CGP 55845 (1 μm)GABAB+6.8 ± 4.5 (14)
    CGP 54626 (1 μm)GABAB+7.4 ± 2.3 (4)
    • +, Reversal of Vc1.1 inhibition; −, no effect; mAChR, muscarinic acetylcholine receptor.

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The Journal of Neuroscience: 28 (43)
Journal of Neuroscience
Vol. 28, Issue 43
22 Oct 2008
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Analgesic α-Conotoxins Vc1.1 and Rg1A Inhibit N-Type Calcium Channels in Rat Sensory Neurons via GABAB Receptor Activation
Brid Callaghan, Alison Haythornthwaite, Géza Berecki, Richard J. Clark, David J. Craik, David J. Adams
Journal of Neuroscience 22 October 2008, 28 (43) 10943-10951; DOI: 10.1523/JNEUROSCI.3594-08.2008

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Analgesic α-Conotoxins Vc1.1 and Rg1A Inhibit N-Type Calcium Channels in Rat Sensory Neurons via GABAB Receptor Activation
Brid Callaghan, Alison Haythornthwaite, Géza Berecki, Richard J. Clark, David J. Craik, David J. Adams
Journal of Neuroscience 22 October 2008, 28 (43) 10943-10951; DOI: 10.1523/JNEUROSCI.3594-08.2008
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