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Molecular Pharmacology

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Research ArticleArticle

Potentiation of High Voltage–Activated Calcium Channels by 4-Aminopyridine Depends on Subunit Composition

Li Li, De-Pei Li, Shao-Rui Chen, Jinjun Chen, Hongzhen Hu and Hui-Lin Pan
Molecular Pharmacology December 2014, 86 (6) 760-772; DOI: https://doi.org/10.1124/mol.114.095505
Li Li
Center for Neuroscience and Pain Research (L.L., D.-P.L, S.-R.C., J.C., H.-L.P.), Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; College of Bioscience and Biotechnology (J.C.), Hunan Agricultural University, Changsha, P.R. China; and Department of Integrative Biology and Pharmacology (H.H.), The University of Texas Medical School, Houston, Texas
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De-Pei Li
Center for Neuroscience and Pain Research (L.L., D.-P.L, S.-R.C., J.C., H.-L.P.), Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; College of Bioscience and Biotechnology (J.C.), Hunan Agricultural University, Changsha, P.R. China; and Department of Integrative Biology and Pharmacology (H.H.), The University of Texas Medical School, Houston, Texas
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Shao-Rui Chen
Center for Neuroscience and Pain Research (L.L., D.-P.L, S.-R.C., J.C., H.-L.P.), Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; College of Bioscience and Biotechnology (J.C.), Hunan Agricultural University, Changsha, P.R. China; and Department of Integrative Biology and Pharmacology (H.H.), The University of Texas Medical School, Houston, Texas
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Jinjun Chen
Center for Neuroscience and Pain Research (L.L., D.-P.L, S.-R.C., J.C., H.-L.P.), Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; College of Bioscience and Biotechnology (J.C.), Hunan Agricultural University, Changsha, P.R. China; and Department of Integrative Biology and Pharmacology (H.H.), The University of Texas Medical School, Houston, Texas
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Hongzhen Hu
Center for Neuroscience and Pain Research (L.L., D.-P.L, S.-R.C., J.C., H.-L.P.), Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; College of Bioscience and Biotechnology (J.C.), Hunan Agricultural University, Changsha, P.R. China; and Department of Integrative Biology and Pharmacology (H.H.), The University of Texas Medical School, Houston, Texas
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Hui-Lin Pan
Center for Neuroscience and Pain Research (L.L., D.-P.L, S.-R.C., J.C., H.-L.P.), Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas; College of Bioscience and Biotechnology (J.C.), Hunan Agricultural University, Changsha, P.R. China; and Department of Integrative Biology and Pharmacology (H.H.), The University of Texas Medical School, Houston, Texas
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Abstract

4-Aminopyridine (4-AP, fampridine) is used clinically to improve neuromuscular function in patients with multiple sclerosis, spinal cord injury, and myasthenia gravis. 4-AP can increase neuromuscular and synaptic transmission by directly stimulating high voltage–activated (HVA) Ca2+ channels independent of its blocking effect on voltage-activated K+ channels. Here we provide new evidence that the potentiating effect of 4-AP on HVA Ca2+ channels depends on the specific combination of voltage-activated calcium channel α1 (Cavα1) and voltage-activated calcium channel β (Cavβ) subunits. Among the four Cavβ subunits examined, Cavβ3 was the most significant subunit involved in the 4-AP–induced potentiation of both L-type and N-type currents. Of particular note, 4-AP at micromolar concentrations selectively potentiated L-type currents reconstituted with Cav1.2, α2δ1, and Cavβ3. In contrast, 4-AP potentiated N-type currents only at much higher concentrations and had little effect on P/Q-type currents. In a phrenic nerve–diaphragm preparation, blocking L-type Ca2+ channels eliminated the potentiating effect of low concentrations of 4-AP on end-plate potentials. Furthermore, 4-AP enhanced the physical interaction of Cav1.2 and Cav2.2 subunits to Cavβ3 and also increased their trafficking to the plasma membrane. Site-directed mutagenesis identified specific regions in the guanylate kinase, HOOK, and C-terminus domains of the Cavβ3 subunit crucial to the ability of 4-AP to potentiate L-type and N-type currents. Our findings indicate that 4-AP potentiates HVA Ca2+ channels by enhancing reciprocal Cav1.2-Cavβ3 and Cav2.2-Cavβ3 interactions. The therapeutic effect of 4-AP on neuromuscular function is probably mediated by its actions on Cavβ3-containing L-type Ca2+ channels.

Footnotes

    • Received August 21, 2014.
    • Accepted September 26, 2014.
  • This work was supported by grants from the National Institutes of Health [R01-HL077400 and R01-NS073935] and by the N.G. and Helen T. Hawkins endowment (to H.-L.P.).

  • dx.doi.org/10.1124/mol.114.095505.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (6)
Molecular Pharmacology
Vol. 86, Issue 6
1 Dec 2014
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Research ArticleArticle

Ca2+ Channel Subunits and 4-Aminopyridine Actions

Li Li, De-Pei Li, Shao-Rui Chen, Jinjun Chen, Hongzhen Hu and Hui-Lin Pan
Molecular Pharmacology December 1, 2014, 86 (6) 760-772; DOI: https://doi.org/10.1124/mol.114.095505

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Research ArticleArticle

Ca2+ Channel Subunits and 4-Aminopyridine Actions

Li Li, De-Pei Li, Shao-Rui Chen, Jinjun Chen, Hongzhen Hu and Hui-Lin Pan
Molecular Pharmacology December 1, 2014, 86 (6) 760-772; DOI: https://doi.org/10.1124/mol.114.095505
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