PMID- 37502910
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240209
DP  - 2023 Jul 17
TI  - Intranasal CRMP2-Ubc9 Inhibitor Regulates Na (V) 1.7 to Alleviate Trigeminal 
      Neuropathic Pain.
LID - 2023.07.16.549195 [pii]
LID - 10.1101/2023.07.16.549195 [doi]
AB  - Dysregulation of voltage-gated sodium Na (V) 1.7 channels in sensory neurons 
      contributes to chronic pain conditions, including trigeminal neuropathic pain. We 
      previously reported that chronic pain results in part from increased SUMOylation 
      of collapsin response mediator protein 2 (CRMP2), leading to an increased 
      CRMP2/Na (V) 1.7 interaction and increased functional activity of Na (V) 1.7. 
      Targeting this feed-forward regulation, we developed compound 194 , which 
      inhibits CRMP2 SUMOylation mediated by the SUMO-conjugating enzyme Ubc9. We 
      further demonstrated that 194 effectively reduces the functional activity of Na 
      (V) 1.7 channels in dorsal root ganglia neurons and alleviated inflammatory and 
      neuropathic pain. Here, we employed a comprehensive array of investigative 
      approaches, encompassing biochemical, pharmacological, genetic, 
      electrophysiological, and behavioral analyses, to assess the functional 
      implications of Na (V) 1.7 regulation by CRMP2 in trigeminal ganglia (TG) 
      neurons. We confirmed the expression of Scn9a , Dpysl2 , and UBE2I within TG 
      neurons. Furthermore, we found an interaction between CRMP2 and Na (V) 1.7, with 
      CRMP2 being SUMOylated in these sensory ganglia. Disrupting CRMP2 SUMOylation 
      with compound 194 uncoupled the CRMP2/Na (V) 1.7 interaction, impeded Na (V) 1.7 
      diffusion on the plasma membrane, and subsequently diminished Na (V) 1.7 
      activity. Compound 194 also led to a reduction in TG neuron excitability. 
      Finally, when intranasally administered to rats with chronic constriction injury 
      of the infraorbital nerve (CCI-ION), 194 significantly decreased nociceptive 
      behaviors. Collectively, our findings underscore the critical role of CRMP2 in 
      regulating Na (V) 1.7 within TG neurons, emphasizing the importance of this 
      indirect modulation in trigeminal neuropathic pain.
FAU - Loya-Lopez, Santiago I
AU  - Loya-Lopez SI
FAU - Allen, Heather N
AU  - Allen HN
FAU - Duran, Paz
AU  - Duran P
AUID- ORCID: 0000-0001-8729-8636
FAU - Calderon-Rivera, Aida
AU  - Calderon-Rivera A
FAU - Gomez, Kimberly
AU  - Gomez K
FAU - Kumar, Upasana
AU  - Kumar U
FAU - Shields, Rory
AU  - Shields R
FAU - Zeng, Rui
AU  - Zeng R
FAU - Dwivedi, Akshat
AU  - Dwivedi A
FAU - Saurabh, Saumya
AU  - Saurabh S
FAU - Korczeniewska, Olga A
AU  - Korczeniewska OA
FAU - Khanna, Rajesh
AU  - Khanna R
AUID- ORCID: 0000-0002-9066-2969
LA  - eng
PT  - Preprint
DEP - 20230717
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
UIN - Pain. 2023 Sep 26;:. PMID: 37751532
PMC - PMC10370107
EDAT- 2023/07/28 06:42
MHDA- 2023/07/28 06:43
PMCR- 2023/07/26
CRDT- 2023/07/28 04:24
PHST- 2023/07/28 06:43 [medline]
PHST- 2023/07/28 06:42 [pubmed]
PHST- 2023/07/28 04:24 [entrez]
PHST- 2023/07/26 00:00 [pmc-release]
AID - 2023.07.16.549195 [pii]
AID - 10.1101/2023.07.16.549195 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2023 Jul 17:2023.07.16.549195. doi: 
      10.1101/2023.07.16.549195.