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Cbd3 peptide

Jennifer Y Xie, Lindsey A Chew, Xiaofang Yang, Yuying Wang, Chaoling Qu, Yue Wang, Lauren M Federici, Stephanie D Fitz, Matthew S Ripsch, Michael R Due, Aubin Moutal, May Khanna, Fletcher A White, Todd W Vanderah, Philip L Johnson, Frank Porreca, Rajesh Khanna
Uncoupling the protein-protein interaction between collapsin response mediator protein 2 (CRMP2) and N-type voltage-gated calcium channel (CaV2.2) with an allosteric CRMP2-derived peptide (CBD3) is antinociceptive in rodent models of inflammatory and neuropathic pain. We investigated the efficacy, duration of action, abuse potential, and neurobehavioral toxicity of an improved mutant CRMP2 peptide. A homopolyarginine (R9)-conjugated CBD3-A6K (R9-CBD3-A6K) peptide inhibited the CaV2.2-CRMP2 interaction in a concentration-dependent fashion and diminished surface expression of CaV2...
September 2016: Pain
Liberty François-Moutal, Yue Wang, Aubin Moutal, Karissa E Cottier, Ohannes K Melemedjian, Xiaofang Yang, Yuying Wang, Weina Ju, Tally M Largent-Milnes, May Khanna, Todd W Vanderah, Rajesh Khanna
Targeting proteins within the N-type voltage-gated calcium channel (CaV2.2) complex has proven to be an effective strategy for developing novel pain therapeutics. We describe a novel peptide aptamer derived from the collapsin response mediator protein 2 (CRMP2), a CaV2.2-regulatory protein. Addition of a 14-carbon myristate group to the peptide (myr-tat-CBD3) tethered it to the membrane of primary sensory neurons near surface CaV2.2. Pull-down studies demonstrated that myr-tat-CBD3 peptide interfered with the CRMP2-CaV2...
July 2015: Pain
Domenico Santoro, Kim Ahrens, Rosanna Marsella, Mariangela Segre
Increased secretion of antimicrobial peptides and cytokines is present in atopic skin. The purpose of this study was to compare the production of β-defensin (cBD)3-like, cathelicidin (cCath) and cytokines in atopic and healthy canine keratinocytes. Seven atopic house dust mites (HDMs) sensitive and five healthy age-matched beagles were used. Keratinocytes were stimulated for 24 h, and the supernatant was collected. A significantly higher production of cBD3-like was present at baseline in atopic compared with healthy keratinocytes, but cBD3-like did not increase after stimulation...
April 2015: Experimental Dermatology
Tatiana Brustovetsky, Jessica J Pellman, Xiao-Fang Yang, Rajesh Khanna, Nickolay Brustovetsky
Collapsin response mediator protein 2 (CRMP2) is traditionally viewed as an axonal growth protein involved in axon/dendrite specification. Here, we describe novel functions of CRMP2. A 15-amino acid peptide from CRMP2, fused to the TAT cell-penetrating motif of the HIV-1 protein, TAT-CBD3, but not CBD3 without TAT, attenuated N-methyl-d-aspartate receptor (NMDAR) activity and protected neurons against glutamate-induced Ca(2+) dysregulation, suggesting the key contribution of CRMP2 in these processes. In addition, TAT-CBD3, but not CBD3 without TAT or TAT-scramble peptide, inhibited increases in cytosolic Ca(2+) mediated by the plasmalemmal Na(+)/Ca(2+) exchanger (NCX) operating in the reverse mode...
March 14, 2014: Journal of Biological Chemistry
G Fischer, B Pan, D Vilceanu, Q H Hogan, H Yu
The Ca(2+) channel-binding domain 3 (CBD3) peptide, derived from the collapsin response mediator protein 2 (CRMP-2), is a recently discovered voltage-gated Ca(2+) channel (VGCC) blocker with a preference for CaV2.2. Rodent administration of CBD3 conjugated to cell penetrating motif TAT (TAT-CBD3) has been shown to reduce pain behavior in inflammatory and neuropathic pain models. However, TAT-CBD3 analgesia has limitations, including short half-life, lack of cellular specificity and undesired potential off-site effects...
January 2014: Gene Therapy
Domenico Santoro, David Bunick, Thomas K Graves, Mariangela Segre
BACKGROUND: Antimicrobial peptides (AMPs) are small immunomodulatory peptides produced by epithelial and immune cells. β-Defensins (BDs) and cathelicidins (Caths) are the most studied AMPs. Recently, increased cutaneous expression of AMPs was reported in atopic humans and in beagles with experimentally induced atopy. HYPOTHESIS/OBJECTIVES: Our goal was to analyse mRNA expression and protein levels of canine (c)BD1-like, cBD2-like/122, cBD3-like, cBD103 and cCath in healthy and naturally affected atopic dogs, with and without active skin infection, along with their distribution in the epidermis using indirect immunofluorescence...
February 2013: Veterinary Dermatology
Andrew D Piekarz, Michael R Due, May Khanna, Bo Wang, Matthew S Ripsch, Ruizhong Wang, Samy O Meroueh, Michael R Vasko, Fletcher A White, Rajesh Khanna
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...
2012: Molecular Pain
Matthew S Ripsch, Carrie J Ballard, May Khanna, Joyce H Hurley, Fletcher A White, Rajesh Khanna
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...
March 2012: Translational Neuroscience
Joel M Brittain, Rui Pan, Haitao You, Tatiana Brustovetsky, Nickolay Brustovetsky, Gerald W Zamponi, Wei-Hua Lee, Rajesh Khanna
Collapsin response mediator protein 2 (CRMP-2), traditionally viewed as an axon/dendrite specification and axonal growth protein, has emerged as nidus in regulation of both pre- and post-synaptic Ca ( 2+) channels. Building on our discovery of the interaction and regulation of Ca ( 2+) channels by CRMP-2, we recently identified a short sequence in CRMP-2 which, when appended to the transduction domain of HIV TAT protein, suppressed acute, inflammatory and neuropathic pain in vivo by functionally uncoupling CRMP-2 from the Ca ( 2+) channel...
January 2012: Channels
Joel M Brittain, Liang Chen, Sarah M Wilson, Tatiana Brustovetsky, Xiang Gao, Nicole M Ashpole, Andrei I Molosh, Haitao You, Andy Hudmon, Anantha Shekhar, Fletcher A White, Gerald W Zamponi, Nickolay Brustovetsky, Jinhui Chen, Rajesh Khanna
Neurological disabilities following traumatic brain injury (TBI) may be due to excitotoxic neuronal loss. The excitotoxic loss of neurons following TBI occurs largely due to hyperactivation of N-methyl-d-aspartate receptors (NMDARs), leading to toxic levels of intracellular Ca(2+). The axon guidance and outgrowth protein collapsin response mediator protein 2 (CRMP2) has been linked to NMDAR trafficking and may be involved in neuronal survival following excitotoxicity. Lentivirus-mediated CRMP2 knockdown or treatment with a CRMP2 peptide fused to HIV TAT protein (TAT-CBD3) blocked neuronal death following glutamate exposure probably via blunting toxicity from delayed calcium deregulation...
October 28, 2011: Journal of Biological Chemistry
Sarah M Wilson, Joel M Brittain, Andrew D Piekarz, Carrie J Ballard, Matthew S Ripsch, Theodore R Cummins, Joyce H Hurley, May Khanna, Nathan M Hammes, Brian C Samuels, Fletcher A White, Rajesh Khanna
The N-type voltage-gated calcium channel (Cav 2.2) has gained immense prominence in the treatment of chronic pain. While decreased channel function is ultimately anti-nociceptive, directly targeting the channel can lead to multiple adverse side effects. Targeting modulators of channel activity may facilitate improved analgesic properties associated with channel block and a broader therapeutic window. A novel interaction between Cav 2.2 and collapsin response mediator protein 2 (CRMP-2) positively regulates channel function by increasing surface trafficking...
September 2011: Channels
Joel M Brittain, Djane B Duarte, Sarah M Wilson, Weiguo Zhu, Carrie Ballard, Philip L Johnson, Naikui Liu, Wenhui Xiong, Matthew S Ripsch, Yuying Wang, Jill C Fehrenbacher, Stephanie D Fitz, May Khanna, Chul-Kyu Park, Brian S Schmutzler, Bo Myung Cheon, Michael R Due, Tatiana Brustovetsky, Nicole M Ashpole, Andy Hudmon, Samy O Meroueh, Cynthia M Hingtgen, Nickolay Brustovetsky, Ru-Rong Ji, Joyce H Hurley, Xiaoming Jin, Anantha Shekhar, Xiao-Ming Xu, Gerry S Oxford, Michael R Vasko, Fletcher A White, Rajesh Khanna
The use of N-type voltage-gated calcium channel (CaV2.2) blockers to treat pain is limited by many physiological side effects. Here we report that inflammatory and neuropathic hypersensitivity can be suppressed by inhibiting the binding of collapsin response mediator protein 2 (CRMP-2) to CaV2.2 and thereby reducing channel function. A peptide of CRMP-2 fused to the HIV transactivator of transcription (TAT) protein (TAT-CBD3) decreased neuropeptide release from sensory neurons and excitatory synaptic transmission in dorsal horn neurons, reduced meningeal blood flow, reduced nocifensive behavior induced by formalin injection or corneal capsaicin application and reversed neuropathic hypersensitivity produced by an antiretroviral drug...
July 2011: Nature Medicine
Domenico Santoro, David Bunick, Thomas K Graves, Karen L Campbell
Antimicrobial peptides (AMPs) are small proteins involved in defense against pathogenic organisms. Defensins and cathelicidin are the most frequently studied human AMPs. Our goals were to determine the distribution of AMPs and evaluate their mRNA expression in normal canine skin. Skin biopsies were taken from six healthy beagles. The relative transcript level of canine cathelicidin (cCath) and β-defensin (cBD)-1, cBD2 and cBD3 mRNA was quantified using quantitative real-time polymerase chain reaction. Indirect immunofluorescence (IIF), using polyclonal antibodies against cBD2, cBD3 and cCath, was used to evaluate protein localization in the skin of healthy dogs...
February 2011: Veterinary Dermatology
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