CRMP-2 Peptide Mediated Decrease of High and Low Voltage-Activated Calcium Channels, Attenuation of Nociceptor Excitability, and Anti-Nociception in a Model of AIDS Therapy-Induced Painful Peripheral Neuropathy
| Autor: | Fletcher A. White, Matthew S. Ripsch, Michael R. Due, Andrew D. Piekarz, May Khanna, Ruizhong Wang, Bo Wang, Samy O. Meroueh, Rajesh Khanna, Michael R. Vasko |
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| Jazyk: | angličtina |
| Předmět: |
Nociception
Plasma protein binding Cell Separation Rats Sprague-Dawley 0302 clinical medicine Calcium Channels N-Type Ganglia Spinal Medicine Peptide sequence 0303 health sciences Neurotransmitter Agents Voltage-dependent calcium channel Nociceptors Peripheral Nervous System Diseases 3. Good health Hyperalgesia Peptide Nociceptor Intercellular Signaling Peptides and Proteins Molecular Medicine tat Gene Products Human Immunodeficiency Virus medicine.symptom Ion Channel Gating lcsh:RB1-214 Protein Binding Molecular Sequence Data Nerve Tissue Proteins Molecular dynamics Molecular Dynamics Simulation 03 medical and health sciences Cellular and Molecular Neuroscience lcsh:Pathology Animals Amino Acid Sequence 030304 developmental biology Acquired Immunodeficiency Syndrome Excitability business.industry Research medicine.disease Molecular medicine Rats Calcium channels Disease Models Animal Peripheral neuropathy Anesthesiology and Pain Medicine Mutagenesis AIDS therapy-induced chronic pain Neuralgia Mutant Proteins business Peptides Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Molecular Pain Molecular Pain, Vol 8, Iss 1, p 54 (2012) |
| ISSN: | 1744-8069 |
| DOI: | 10.1186/1744-8069-8-54 |
| Popis: | Background: The ubiquity of protein-protein interactions in biological signaling offers ample opportunities for therapeutic intervention. We previously identified a peptide, designated CBD3, that suppressed inflammatory and neuropathic behavioral hypersensitivity in rodents by inhibiting the ability of collapsin response mediator protein 2 (CRMP-2) to bind to N-type voltage-activated calcium channels (CaV2.2) [Brittain et al. Nature Medicine 17:822–829 (2011)]. Results and discussion: Here, we utilized SPOTScan analysis to identify an optimized variation of the CBD3 peptide (CBD3A6K) that bound with greater affinity to Ca2+ channels. Molecular dynamics simulations demonstrated that the CBD3A6K peptide was more stable and less prone to the unfolding observed with the parent CBD3 peptide. This mutant peptide, conjugated to the cell penetrating motif of the HIV transduction domain protein TAT, exhibited greater anti-nociception in a rodent model of AIDS therapy-induced peripheral neuropathy when compared to the parent TAT-CBD3 peptide. Remarkably, intraperitoneal administration of TAT-CBD3A6K produced none of the minor side effects (i.e. tail kinking, body contortion) observed with the parent peptide. Interestingly, excitability of dissociated small diameter sensory neurons isolated from rats was also reduced by TAT-CBD3A6K peptide suggesting that suppression of excitability may be due to inhibition of T- and R-type Ca2+ channels. TAT-CBD3A6K had no effect on depolarization-evoked calcitonin gene related peptide (CGRP) release compared to vehicle control. Conclusions: Collectively, these results establish TAT-CBD3A6K as a peptide therapeutic with greater efficacy in an AIDS therapy-induced model of peripheral neuropathy than its parent peptide, TAT-CBD3. Structural modifications of the CBD3 scaffold peptide may result in peptides with selectivity against a particular subset of voltage-gated calcium channels resulting in a multipharmacology of action on the target. |
| Databáze: | OpenAIRE |
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