Anion exchanger 3 in dorsal root ganglion contributes to nerve injury-induced chronic mechanical allodynia and thermal hyperalgesia

Pérez-Rodríguez, Marian Jesabel; Velázquez-Lagunas, Isabel; Pluma-Pluma, Alejandro; Barragán-Iglesias, Paulino; Granados‐Soto, Vinicio

doi:10.1111/jphp.12868

Cited by 2 publications

(3 citation statements)

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“…There were evidences that AE3 was present in DRG and participates in the development and maintenance of short and long-lasting formalin-induced nociception (19). Furthermore, it also contributed to mechanical allodynia and thermal hyperalgesia in neuropathic rats (20). Therefore, we speculate that AE3 is also related to the occurrence of diabetic neuropathy pain, and its mechanism is more worthy of our study.…”

Section: Discussionmentioning

confidence: 76%

“…DRG neurons express several types of chloride channel belonging to different channel families, including ligand-gated, GABA, Ca2 + -activated chloride channels of the anoctamin (also known as TMEM16), CLC chloride channels and transporters, CFTR (cystic fibrosis transmembrane conductance regulator), Best1 (bestrophin) family, as well as VRACs (volume-regulated anion channels). Besides, Na + -independent Cl -HCO3anion exchanger, which is proved for the intracellular Claccumulation, is expressed in 60% of peptidergic and 30% of non-peptidergic DRG neurons (20). However, the Cl -HCO3ion channel is rarely studied in diabetic neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

“…Although the protein sequence of HCO3transpont-like transmembrane domain of AE1 has a gap of 4 amino acids (aa 555-558), the four AEs have the same domain in the C-terminal. However, only AE3 has been proved to present in DRG; AE3 expression enhanced during short and long-lasting formalin- induced nociception (19), and spared nerve injury enhanced base-line AE3 expression in L4 and L5 DRGs (20). Since PRDX6 overexpressed in the D-DRG and could be modified by S-palmitoylation, we demonstrated that the palmitoylation of PRDX6 participated in the interaction between PRDX6 and the C-terminal tail of AE3 in DRG, which could activate the influx of Cland extra-flux of HCO3 -, resulting in pain and decrease of pH (Figure 6).…”

Section: Prdx6 Interacts With Ae3 In Nervous Systemmentioning

confidence: 99%

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PRDX6: A protein bridging S-palmitoylation and diabetic neuropathy

Cao

Wang²,

Zhan³

et al. 2022

Front. Endocrinol.

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Diabetic neuropathy is regarded as one of the most debilitating outcomes of diabetes. It can affect both the peripheral and central nervous systems, leading to pain, decreased motility, cognitive decline, and dementia. S-palmitoylation is a reversible posttranslational lipid modification, and its dysregulation has been implicated in metabolic syndrome, cancers, neurological disorders, and infections. However, the role of S-palmitoylation in diabetic neuropathy remains unclear. Here we demonstrate a potential association between activating protein palmitoylation and diabetic neuropathy. We compared the proteomic data of lumbar dorsal root ganglia (DRG) of diabetes mice and palmitoylome profiling data of the HUVEC cell line. The mapping results identified peroxiredoxin-6 (PRDX6) as a novel target in diabetic neuropathy, whose biological mechanism was associated with S-palmitoylation. Bioinformatic prediction revealed that PRDX6 had two palmitoylation sites, Cys47 and Cys91. Immunofluorescence results indicated PRDX6 translocating between the cytoplasm and cell membrane. Protein function analysis proposed that increased palmitoylation could competitively inhibit the formation of disulfide-bond between Cys47 and Cys91 and change the spatial topology of PRDX6 protein. Cl–HCO3- anion exchanger 3 (AE3) was one of the AE family members, which was proved to express in DRG. AE3 activity evoked Cl- influx in neurons which was generally associated with increased excitability and susceptibility to pain. We demonstrated that the S-palmitoylation status of Cys47 could affect the interaction between PRDX6 and the C-terminal domain of AE3, thereby regulating the activity of AE3 anion exchanger enzyme in the nervous system. The results highlight a central role for PRDX6 palmitoylation in protection against diabetic neuropathy.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Prdx6 Interacts With Ae3 In Nervous Systemmentioning

confidence: 99%

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