A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors

Pain
Liberty François-MoutalRajesh Khanna

Abstract

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-CaV2.2 interaction. Quantitative confocal immunofluorescence revealed a pronounced reduction of CaV2.2 trafficking after myr-tat-CBD3 treatment and increased efficiency in disrupting CRMP2-CaV2.2 colocalization compared with peptide tat-CBD3. Consequently, myr-tat-CBD3 inhibited depolarization-induced calcium influx in sensory neurons. Voltage clamp electrophysiology experiments revealed a reduction of Ca, but not Na, currents in sensory neurons after myr-tat-CBD3 exposure. Current clamp electrophysiology experiments demonstrated a reduction in excitability of small-diameter dorsal root ganglion neurons after exposure to myr-tat-CBD3. Myr-tat-CBD3 was effective in significantly attenuating carrageenan-induced thermal...Continue Reading

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Citations

Mar 21, 2017·British Journal of Pharmacology·Ryan PatelAnthony H Dickenson
Mar 13, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kerri D PryceArin Bhattacharjee
Jul 1, 2017·Molecular Neurobiology·Aubin MoutalRajesh Khanna
Dec 20, 2018·Molecular Neurobiology·Jie YuRajesh Khanna
Oct 27, 2018·Neuronal Signaling·Lindsey A Chew, Rajesh Khanna
Nov 5, 2019·Channels·Aubin MoutalRajesh Khanna
Jul 3, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Gabriella MacDougallBruno P Meloni
Aug 11, 2020·Pain·Kimberly GomezRajesh Khanna
Apr 16, 2018·Neuroscience·Aubin MoutalRajesh Khanna
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Jul 23, 2020·ACS Chemical Neuroscience·Rajesh KhannaMarcel Patek
Nov 11, 2021·Science Translational Medicine·Song CaiRajesh Khanna

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