6533b856fe1ef96bd12b279c

RESEARCH PRODUCT

TAFA4 relieves injury-induced mechanical hypersensitivity through LDL receptors and modulation of spinal A-type K+ current

Catarina SantosRafaelle RossignolAna ReyndersJean-yves SpringaelPascale MalapertIrène MaricsFrancis CastetsMarc ParmentierAndrew J. SaurinAziz MoqrichSophie UgoliniNadine ClercJean-marc GoaillardSungjae YooAbderazzak El KhallouqiAude CharronStéphane Gaillard

subject

Spinal Cord Dorsal HornSNiSpinal neuron[SDV]Life Sciences [q-bio]AnalgesicPainCHO CellsPharmacologyInhibitory postsynaptic potentialGeneral Biochemistry Genetics and Molecular BiologyTAFA4Mice03 medical and health sciencesCricetulus0302 clinical medicineAnimalsHumansMedicine030304 developmental biologyLDL-receptors0303 health sciencesbusiness.industryIA and IhNerve injury3. Good healthHEK293 CellsRAW 264.7 CellsReceptors LDLHyperalgesiainjury-induced mechanical painLDL receptorPotassiumExcitatory postsynaptic potentialCytokinesgating neuronsmedicine.symptomRAPbusiness030217 neurology & neurosurgeryLipoprotein

description

Pain, whether acute or persistent, is a serious medical problem worldwide. However, its management remains unsatisfactory, and new analgesic molecules are required. We show here that TAFA4 reverses inflammatory, postoperative, and spared nerve injury (SNI)-induced mechanical hypersensitivity in male and female mice. TAFA4 requires functional low-density lipoprotein receptor-related proteins (LRPs) because their inhibition by RAP (receptor-associated protein) dose-dependently abolishes its antihypersensitive actions. SNI selectively decreases A-type K+ current (IA) in spinal lamina II outer excitatory interneurons (L-IIo ExINs) and induces a concomitant increase in IA and decrease in hyperpolarization-activated current (Ih) in lamina II inner inhibitory interneurons (L-IIi InhINs). Remarkably, SNI-induced ion current alterations in both IN subtypes were rescued by TAFA4 in an LRP-dependent manner. We provide insights into the mechanism by which TAFA4 reverses injury-induced mechanical hypersensitivity by restoring normal spinal neuron activity and highlight the considerable potential of TAFA4 as a treatment for injury-induced mechanical pain.

yearjournalcountryeditionlanguage
2021-10-01Cell Reports
https://doi.org/10.1016/j.celrep.2021.109884