Dysregulation of CRMP2 Post-Translational Modifications Drive Its Pathological Functions

Moutal, Aubin; White, Katherine A.; Chefdeville, Aude; Laufmann, Rachel N.; Vitiello, Peter F.; Feinstein, Douglas L.; Weimer, Jill M.; Khanna, Rajesh

doi:10.1007/s12035-019-1568-4

Cited by 67 publications

(111 citation statements)

References 188 publications

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“…Overall, our data and recent findings by others implicate SUMOylation as an emerging mechanism for regulating signalling in the afferent pain pathway that may potentially be exploited towards development of new therapeutic strategies [26].…”

Section: Resultssupporting

confidence: 77%

SUMOylation regulates USP5-Cav3.2 calcium channel interactions

et al. 2019

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Cav3.2 calcium channels play a key role in nociceptive signaling in the primary afferent pain pathway. We have previously reported the regulation of Cav3.2 calcium channels by the deubiquitinase USP5 and its importance for regulating peripheral transmission of pain signals. Here we describe the regulation of the Cav3.2-USP5 interaction by SUMOylation. We show that endogenous USP5 protein expressed in dorsal root ganglia undergoes SUMOylation, and the level of USP5 SUMOylation is reduced following peripheral nerve injury. SUMO prediction software identified several putative lysines that have the propensity to be targets for SUMO conjugation. A series of single lysine substitutions in an mCherry tagged USP5 construct followed by expression in tsA-201 cells identified lysine K113 as a key target for USP5 SUMO2/3 modification. Finally, Cav3.2 calcium channel immunoprecipitates revealed a stronger interaction of Cav3.2 with a SUMO2/3 resistant USP5-K113R mutant, indicating that SUMO2/3 modification of USP5 reduces its affinity for the calcium channel Cav3.2. Collectively, our data suggest that dysregulation of USP5 SUMOylation after peripheral nerve injury may contribute to the well described alteration in Cav3.2 channel activity during neuropathic pain states.

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Section: Resultssupporting

confidence: 77%

SUMOylation regulates USP5-Cav3.2 calcium channel interactions

et al. 2019

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“…In chronic pain, proteins regulating the N-type (CaV2.2) VGCCs can modulate nociception [1]. One such protein is the collapsin response mediator protein 2 (CRMP2) [3][4][5][6][7][8][9][10][11][12][13][14][15]. Our continuing studies have established CRMP2 as a bona fide binding partner and regulator of the presynaptic trafficking of CaV2.2 [4,8,13,[15][16][17][18].…”

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confidence: 99%

Activity of T-type calcium channels is independent of CRMP2 in sensory neurons

et al. 2019

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Amongst the regulators of voltage-gated ion channels is the collapsin response mediator protein 2 (CRMP2). CRMP2 regulation of the activity and trafficking of NaV1.7 voltage-gated sodium channels as well as the N-type (CaV2.2) voltage-gated calcium channel (VGCC) has been reported. On the other hand, CRMP2 does not appear to regulate L-(CaV1.x), P/Q-(CaV2.1), and R-(CaV2.3) type high VGCCs. Whether CRMP2 regulates low VGCCs remains an open question. Here, we asked if CRMP2 could regulate the low voltage-gated (T-type/CaV3.x) channels in sensory neurons. Reducing CRMP2 protein levels with short interfering RNAs yielded no change in macroscopic currents carried by T-type channels. No change in biophysical properties of the T-type currents was noted. Future studies pursuing CRMP2 druggability in neuropathic pain will benefit from the findings that CRMP2 regulates only the N-type (CaV2.2) calcium channels.

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“…At this location, CRMP2 controls the presynaptic levels of both CaV2.2 and NaV1.7, two voltage gated ion channels essential for nociceptive signal transmission [3]. Actions of CRMP2 are tightly regulated by post-translational modifications [1]. In chronic neuropathic pain, we found that CRMP2 phosphorylation by cyclin-dependent kinase 5 (Cdk5) on Serine 522 (S522) was sufficient for mechanical allodynia [2] through the facilitation of CaV2.2 and NaV1.7 function [4][5][6][7][8].…”

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confidence: 97%

“…Edonerpic maleate was found to disrupt CRMP2 tetramers [10]. Our previous body of work has established a role for phosphorylated and non-phosphorylated CRMP2 in control of voltage-gated calcium and sodium channels [1,[3][4][5][6][7][8][13][14][15][16][17][18][19][20][21][22]. Therefore, we tested the effect of edonerpic maleate on these channels.…”

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Evaluation of edonerpic maleate as a CRMP2 inhibitor for pain relief

et al. 2019

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We have previously reported that the microtubule-associated collapsin response mediator protein 2 (CRMP2) is necessary for the expression of chronic pain. CRMP2 achieves this control of nociceptive signaling by virtue of its ability to regulate voltage-gated calcium and sodium channels. To date, however, no drugs exist that target CRMP2. Recently, the small molecule edonerpic maleate (1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate), a candidate therapeutic for Alzheimer's disease was reported to be a novel CRMP2 binding compound with the potential to decrease its phosphorylation level in cortical tissues in vivo. Here we sought to determine the mechanism of action of edonerpic maleate and test its possible effect in a rodent model of chronic pain. We observed: (i) no binding between human CRMP2 and edonerpic maleate; (ii) edonerpic maleate had no effect on CRMP2 expression and phosphorylation in dorsal root ganglion (DRG) neurons; (iii) edonerpic maleate-decreased calcium but increased sodium current density in DRG neurons; and (iv) edonerpic maleate was ineffective in reversing post-surgical allodynia in male and female mice. Thus, while CRMP2 inhibiting compounds remain a viable strategy for developing new mechanism-based pain inhibitors, edonerpic maleate is an unlikely candidate.

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Dysregulation of CRMP2 Post-Translational Modifications Drive Its Pathological Functions

Cited by 67 publications

References 188 publications

SUMOylation regulates USP5-Cav3.2 calcium channel interactions

SUMOylation regulates USP5-Cav3.2 calcium channel interactions

Activity of T-type calcium channels is independent of CRMP2 in sensory neurons

Evaluation of edonerpic maleate as a CRMP2 inhibitor for pain relief

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