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A peptide uncoupling CRMP-2 from the presynaptic Ca2+ channel complex demonstrates efficacy in animal models of migraine and AIDS therapy-induced neuropathy

Matthew Ripsch
  • Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, USA
  • Department of Anesthesia, Indiana University School of Medicine, Indianapolis, USA
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/ Carrie Ballard
  • Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, USA
  • Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, USA
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/ May Khanna
  • Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, USA
  • Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, USA
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/ Joyce Hurley
  • Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, USA
  • Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, USA
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/ Fletcher White
  • Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, USA
  • Department of Anesthesia, Indiana University School of Medicine, Indianapolis, USA
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/ Rajesh Khanna
  • Program in Medical Neurosciences, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, USA
  • Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, USA
  • Sophia Therapeutics LLC, 351 West 10th Street, Indianapolis, Indiana, 46202, USA
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Published Online: 2012-03-14 | DOI: https://doi.org/10.2478/s13380-012-0002-4

Abstract

Biological, genetic, and clinical data provide compelling proof for N-type voltage-gated calcium channels (CaV2.2) as therapeutic targets for chronic pain. While decreasing channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse effects. Targeting regulators of channel activity may facilitate improved analgesic properties associated with channel block and afford a broader therapeutic window. Towards this end, we recently identified a short peptide, designated CBD3, derived from collapsin response mediator protein 2 (CRMP-2) that suppressed inflammatory and neuropathic hypersensitivity by inhibiting CRMP-2 binding to CaV2.2 [Brittain et al., Nature Medicine 17:822–829 (2011)]. Rodents administered CBD3 intraperitoneally, fused to the HIV TAT protein cell penetrating domain, exhibited antinociception lasting ∼4 hours highlighting potential instability, limited oral bioavailability, and/or rapid elimination of peptide. This report focuses on improving upon the parental CBD3 peptide. Using SPOTScan analysis of synthetic versions of the parental CBD3 peptide, we identified peptides harboring single amino acid mutations that bound with greater affinity to CaV2.2. One such peptide, harboring a phenylalanine instead of glycine (G14F), was tested in rodent models of migraine and neuropathic pain. In vivo laser Doppler blood flowmetry measure of capsaicin-induced meningeal vascular responses related to headache pain was almost completely suppressed by dural application of the G14F peptide. The G14F mutant peptide, administered intraperitoneally, also exhibited greater antinociception in Stavudine (2′-3′-didehydro-2′-3′-dideoxythymidine (d4T)/Zerit®) model of AIDS therapy-induced peripheral neuropathy compared to the parent CBD3 peptide. These results demonstrate the patent translational value of small biologic drugs targeting CaV2.2 for management of clinical pain.

Keywords: N-type calcium channel; CRMP-2; Uncoupling peptide; Meningeal blood flow; Migraine model; d4T/Zerit/Stavudine; NTR; AIDS therapy-induced neuropathic pain; Chronic pain

  • [1] Institute of medicine report from the committee on advancing pain research care and education, Relieving pain in America: A blueprint for transforming prevention, care, education and research, The National Academies Press, 2011 Google Scholar

  • [2] Snutch T. P., Targeting chronic and neuropathic pain: the N-type calcium channel comes of age, NeuroRx, 2005, 2, 662–670 http://dx.doi.org/10.1602/neurorx.2.4.662CrossrefGoogle Scholar

  • [3] Catterall W. A., Few A. P., Calcium channel regulation and presynaptic plasticity, Neuron, 2008, 59, 882–901 http://dx.doi.org/10.1016/j.neuron.2008.09.005Web of ScienceCrossrefGoogle Scholar

  • [4] Saegusa H., Kurihara T., Zong S., Kazuno A., Matsuda Y., Nonaka T. et al., Suppression of inflammatory and neuropathic pain symptoms in mice lacking the N-type Ca2+ channel, EMBO J., 2001, 20, 2349–2356 http://dx.doi.org/10.1093/emboj/20.10.2349CrossrefGoogle Scholar

  • [5] Cizkova D., Marsala J., Lukacova N., Marsala M., Jergova S., Orendacova J. et al., Localization of N-type Ca2+ channels in the rat spinal cord following chronic constrictive nerve injury, Exp. Brain Res., 2002, 147, 456–463 http://dx.doi.org/10.1007/s00221-002-1217-3CrossrefGoogle Scholar

  • [6] Bell T. J., Thaler C., Castiglioni A. J., Helton T. D., Lipscombe D., Cellspecific alternative splicing increases calcium channel current density in the pain pathway, Neuron, 2004, 41, 127–138 http://dx.doi.org/10.1016/S0896-6273(03)00801-8CrossrefGoogle Scholar

  • [7] Altier C., Dale C. S., Kisilevsky A. E., Chapman K., Castiglioni A. J., Matthews E. A. et al., Differential role of N-type calcium channel splice isoforms in pain, J. Neurosci., 2007, 27, 6363–6373 http://dx.doi.org/10.1523/JNEUROSCI.0307-07.2007CrossrefGoogle Scholar

  • [8] Zamponi G. W., Feng Z. P., Zhang L., Pajouhesh H., Ding Y., Belardetti F. et al. Scaffold-based design and synthesis of potent N-type calcium channel blockers, Bioorg. Med. Chem. Lett., 2009, 19, 6467–6472 http://dx.doi.org/10.1016/j.bmcl.2009.09.008CrossrefGoogle Scholar

  • [9] Zamponi G. W., Lewis R. J., Todorovic S. M., Arneric S. P., Snutch T. P., Role of voltage-gated calcium channels in ascending pain pathways, Brain Res. Rev., 2009, 60, 84–89 http://dx.doi.org/10.1016/j.brainresrev.2008.12.021Web of ScienceCrossrefGoogle Scholar

  • [10] Swensen A. M., Herrington J., Bugianesi R. M., Dai G., Haedo R. J., Ratliff K. S. et al., Characterization of the substituted N-triazole oxindole, TROX-1, a small molecule, state-dependent inhibitor of CaV2 calcium channels, Mol. Pharmacol., 2011 epub ahead of print Google Scholar

  • [11] Abbadie C., McManus O. B., Sun S. Y., Bugianesi R. M., Dai G., Haedo R. J. et al., Analgesic effects of a substituted N-triazole oxindole (TROX-1), a state-dependent, voltage-gated calcium channel 2 blocker, J. Pharmacol. Exp. Ther., 2010, 334, 545–555 http://dx.doi.org/10.1124/jpet.110.166363CrossrefWeb of ScienceGoogle Scholar

  • [12] Bauer C. S., Nieto-Rostro M., Rahman W., Tran-Van-Minh A., Ferron L., Douglas L. et al., The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin, J. Neurosci., 2009, 29, 4076–4088 http://dx.doi.org/10.1523/JNEUROSCI.0356-09.2009Web of ScienceGoogle Scholar

  • [13] Brittain J. M., Piekarz A. D., Wang Y., Kondo T., Cummins T. R., Khanna R., An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltagegated Ca2+ channels, J. Biol. Chem., 2009, 284, 31375–31390 http://dx.doi.org/10.1074/jbc.M109.009951Web of ScienceCrossrefGoogle Scholar

  • [14] Chi X. X., Schmutzler B. S., Brittain J. M., Hingtgen C. M., Nicol G. D., Khanna R., Regulation of N-type voltage-gated calcium (CaV2.2) channels and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons, J. Cell. Sci., 2009, 23, 4351–4362 http://dx.doi.org/10.1242/jcs.053280Web of ScienceCrossrefGoogle Scholar

  • [15] Hensley K., Venkova K., Christov A., Gunning W., Park J., Collapsin response mediator protein-2: an emerging pathologic feature and therapeutic target for neurodisease indications, Mol. Neurobiol., 2011, 43, 180–191 http://dx.doi.org/10.1007/s12035-011-8166-4CrossrefWeb of ScienceGoogle Scholar

  • [16] Inagaki N., Chihara K., Arimura N., Ménager C., Kawano Y., Matsuo N. et al., CRMP-2 induces axons in cultured hippocampal neurons, Nat. Neurosci., 2001, 4, 781–782 http://dx.doi.org/10.1038/90476CrossrefGoogle Scholar

  • [17] Arimura N., Hattori A., Kimura T., Nakamuta S., Funahashi Y., Hirotsune S. et al., CRMP-2 directly binds to cytoplasmic dynein and interferes with its activity, J. Neurochem., 2009, 111, 380–390 http://dx.doi.org/10.1111/j.1471-4159.2009.06317.xWeb of ScienceCrossrefGoogle Scholar

  • [18] Morita T., Sobue K., Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway, J. Biol. Chem., 2009, 284, 27734–27745 http://dx.doi.org/10.1074/jbc.M109.008177Web of ScienceGoogle Scholar

  • [19] Yoshimura T., Kawano Y., Arimura N., Kawabata S., Kikuchi A., Kaibuchi K., GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity, Cell, 2005, 120, 137–149 http://dx.doi.org/10.1016/j.cell.2004.11.012CrossrefGoogle Scholar

  • [20] Wang Y., Brittain J. M., Wilson S. M., Khanna R., Emerging roles of collapsin response mediator proteins (CRMPs) as regulators of voltage-gated calcium channels and synaptic transmission, Commun. Integr. Biol., 2010, 3, 1–4 http://dx.doi.org/10.4161/cib.3.1.9694CrossrefGoogle Scholar

  • [21] Brittain J. M., Duarte D. B., Wilson S. M., Zhu W., Ballard C., Johnson P. L. et al., Suppression of inflammatory and neuropathic pain by uncoupling CRMP-2 from the presynaptic Ca(2+) channel complex, Nat. Med., 2011, 17, 822–829 http://dx.doi.org/10.1038/nm.2345Web of ScienceGoogle Scholar

  • [22] Wilson S. M., Brittain J. M., Piekarz A. D., Ballard C. J., Ripsch M. S., Cummins T. R. et al., Further insights into the antinociceptive potential of a peptide disrupting the N-type calcium channel-CRMP-2 signaling complex, Channels (Austin), 2011, 5, 449–456 http://dx.doi.org/10.4161/chan.5.5.17363Web of ScienceCrossrefGoogle Scholar

  • [23] Kurosawa M., Messlinger K., Pawlak M., Schmidt R. F., Increase of meningeal blood flow after electrical stimulation of rat dura mater encephali: mediation by calcitonin gene-related peptide, Br. J. Pharmacol., 1995, 114, 1397–1402 Google Scholar

  • [24] Gottselig R., Messlinger K., Noxious chemical stimulation of rat facial mucosa increases intracranial blood flow through a trigemino-parasympathetic reflex—an experimental model for vascular dysfunctions in cluster headache, Cephalalgia, 2004, 24, 206–214 http://dx.doi.org/10.1111/j.1468-2982.2004.00649.xCrossrefGoogle Scholar

  • [25] Joseph E. K., Chen X., Khasar S. G., Levine J. D., Novel mechanism of enhanced nociception in a model of AIDS therapy-induced painful peripheral neuropathy in the rat, Pain, 2004, 107, 147–158 http://dx.doi.org/10.1016/j.pain.2003.10.010CrossrefGoogle Scholar

  • [26] LaMotte R. H., Friedman R. M., Lu C., Khalsa P. S., Srinivasan M. A., Raised object on a planar surface stroked across the fingerpad: responses of cutaneous mechanoreceptors to shape and orientation, J. Neurophysiol., 1998, 80, 2446–2466 Google Scholar

  • [27] Ma C., Shu Y., Zheng Z., Chen Y., Yao H., Greenquist K. W. et al., Similar electrophysiological changes in axotomized and neighboring intact dorsal root ganglion neurons, J. Neurophysiol., 2003, 89, 1588–1602 http://dx.doi.org/10.1152/jn.00855.2002CrossrefGoogle Scholar

  • [28] Goadsby P. J., Calcitonin gene-related peptide (CGRP) antagonists and migraine: is this a new era?, Neurology, 2008, 70, 1300–1301 http://dx.doi.org/10.1212/01.wnl.0000309214.25038.fdCrossrefGoogle Scholar

  • [29] Olesen J., Diener H. C., Husstedt I. W., Goadsby P. J., Hall D., Meier U. et al., Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine, N. Engl. J. Med., 2004, 350, 1104–1110 http://dx.doi.org/10.1056/NEJMoa030505CrossrefGoogle Scholar

  • [30] Xiao Y., Richter J. A., Hurley J. H., Release of glutamate and CGRP from trigeminal ganglion neurons: Role of calcium channels and 5-HT1 receptor signaling, Mol. Pain, 2008, 4, 12 http://dx.doi.org/10.1186/1744-8069-4-12Web of ScienceGoogle Scholar

  • [31] Kunkler P. E., Ballard C. J., Oxford G. S., Hurley J. H., TRPA1 receptors mediate environmental irritant-induced meningeal vasodilatation, Pain, 2011, 152, 38–44 http://dx.doi.org/10.1016/j.pain.2010.08.021Web of ScienceGoogle Scholar

  • [32] Bhangoo S. K., Ripsch M. S., Buchanan D. J., Miller R. J., White F. A., Increased chemokine signaling in a model of HIV1-associated peripheral neuropathy, Mol. Pain, 2009, 5, 48 http://dx.doi.org/10.1186/1744-8069-5-48Google Scholar

  • [33] Westenbroek R. E., Hoskins L., Catterall W. A.. Localization of Ca2+ channel subtypes on rat spinal motor neurons, interneurons, and nerve terminals, J. Neurosci., 1998, 18, 6319–6330 Google Scholar

  • [34] Kerr L. M., Filloux F., Olivera B. M., Jackson H., Wamsley J. K., Autoradiographic localization of calcium channels with [125I] omega-conotoxin in rat brain, Eur. J. Pharmacol., 1988, 146, 181–183 http://dx.doi.org/10.1016/0014-2999(88)90501-8CrossrefGoogle Scholar

  • [35] Heinke B., Balzer E., Sandkuhler J., Pre- and postsynaptic contributions of voltage-dependent Ca2+ channels to nociceptive transmission in rat spinal lamina I neurons, Eur. J. Neurosci., 2004, 19, 103–111 http://dx.doi.org/10.1046/j.1460-9568.2003.03083.xCrossrefGoogle Scholar

  • [36] Akerman S., Williamson D. J., Goadsby P. J., Voltage-dependent calcium channels are involved in neurogenic dural vasodilatation via a presynaptic transmitter release mechanism, Br. J. Pharmacol., 2003, 140, 558–566 http://dx.doi.org/10.1038/sj.bjp.0705456CrossrefGoogle Scholar

  • [37] Dux M., Santha P., Jancso G., Capsaicin-sensitive neurogenic sensory vasodilatation in the dura mater of the rat, J. Physiol., 2003, 552, 859–867 http://dx.doi.org/10.1113/jphysiol.2003.050633CrossrefGoogle Scholar

  • [38] Zimmermann K., Reeh P. W., Averbeck B., S+ -flurbiprofen but not 5-HT1 agonists suppress basal and stimulated CGRP and PGE2 release from isolated rat dura mater, Pain, 2003, 103, 313–320 http://dx.doi.org/10.1016/S0304-3959(02)00459-1CrossrefGoogle Scholar

  • [39] Peitl B., Petho G., Porszasz R., Nemeth J., Szolcsanyi J., Capsaicininsensitive sensory-efferent meningeal vasodilatation evoked by electrical stimulation of trigeminal nerve fibres in the rat, Br. J. Pharmacol., 1999, 127, 457–467 http://dx.doi.org/10.1038/sj.bjp.0702561CrossrefGoogle Scholar

  • [40] Eikermann-Haerter K., Moskowitz M. A., Animal models of migraine headache and aura, Curr. Opin. Neurol., 2008, 21, 294–300 http://dx.doi.org/10.1097/WCO.0b013e3282fc25deCrossrefGoogle Scholar

  • [41] Reuter U., Sanchez del R. M., Moskowitz M. A., Experimental models of migraine, Funct. Neurol., 2000, 15(Suppl 3), 9–18 Google Scholar

  • [42] Panconesi A., Bartolozzi M. L., Guidi L., Migraine pain: reflections against vasodilatation, J. Headache Pain, 2009, 10, 317–325 http://dx.doi.org/10.1007/s10194-009-0130-6CrossrefGoogle Scholar

  • [43] Strassman A. M., Levy D., Response properties of dural nociceptors in relation to headache, J. Neurophysiol., 2006, 95, 1298–1306 http://dx.doi.org/10.1152/jn.01293.2005CrossrefGoogle Scholar

  • [44] Moyle G. J., Sadler M., Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management, Drug Saf., 1998, 19, 481–494 http://dx.doi.org/10.2165/00002018-199819060-00005CrossrefGoogle Scholar

  • [45] Deo R. C., Schmidt E. F., Elhabazi A., Togashi H., Burley S. K., Strittmatter S. M., Structural bases for CRMP function in plexin-dependent semaphorin3A signaling, EMBO J., 2004, 23, 9–22 http://dx.doi.org/10.1038/sj.emboj.7600021CrossrefGoogle Scholar

About the article

Published Online: 2012-03-14

Published in Print: 2012-03-01


Citation Information: Translational Neuroscience, Volume 3, Issue 1, Pages 1–8, ISSN (Online) 2081-6936, ISSN (Print) 2081-3856, DOI: https://doi.org/10.2478/s13380-012-0002-4.

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© 2012 Versita Warsaw. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. BY-NC-ND 3.0

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