Homology‐guided mutational analysis reveals the functional requirements for antinociceptive specificity of collapsin response mediator protein 2‐derived peptides

• DOI: 10.1111/bph.13737
• Publication Date: 2017-02-05T22:52:45Z
• Authors: Aubin Moutal; Wennan Li; Yue Wang; Weina Ju; Shizhen Luo; Song Cai; Liberty François‐...; Samantha Perez‐Mi...; Jackie Hu; Erik T Dustrude; Todd W Vanderah; Vijay Gokhale; May Khanna; Rajesh Khanna
• Keywords: Dorsal root ganglion

N-type voltage-gated calcium (Cav 2.2) channels are critical determinants of increased neuronal excitability and neurotransmission accompanying persistent neuropathic pain. Although Cav 2.2 channel antagonists recommended as first-line treatment for pain, calcium-current blocking gabapentinoids inadequately alleviate chronic pain symptoms often exhibit numerous side effects. Collapsin response mediator protein 2 (CRMP2) targets to the sensory neuron membrane allosterically modulates their function. A 15-amino-acid peptide (CBD3), derived from CRMP2, disrupts functional protein-protein interaction between CRMP2 inhibit influx, transmitter release acute, inflammatory Here, we have mapped minimal domain CBD3 necessary its antinociceptive potential.Truncated well homology-guided mutant versions were generated assessed using depolarization-evoked influx in rat dorsal root ganglion neurons, binding channels, whole-cell voltage clamp electrophysiology behavioural effects two models experimental pain: post-surgical HIV-induced neuropathy induced by viral glycoprotein 120.The first six amino acids within accounted all vitro activity antinociception. Spinal administration a prototypical (TAT-CBD3-L5M) reversed behaviours. Homology-guided mutational analyses these identified at least residues, Ala1 Arg4, being antinociception models.These results identify an scaffold core that can be used development low MW mimetics CBD3.This article is part themed section on Recent Advances Targeting Ion Channels Treat Chronic Pain. To view other articles this visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.