A Novel Target for Analgesic Substances: Physiological Role of Na,K-ATPase As The Signal Transducer

Valentina A. Penniyaynen¹Dmitriy M. Samosvat²Vera B. Plakhova^1,3Svetlana A. Podzorova¹Anna V. Berintseva¹Irina P. Butkevich¹Viktor A. Mikhailenko¹Georgy G. Zegrya^1,2MA Ke^4*Ilya V. Dukhovlinov⁵Boris V. Krylov^1*Ilya V. Rogachevskii¹

• ¹FGBUN Institut fiziologii imeni I P Pavlova Rossijskoj akademii nauk, Saint Petersburg, Russia
• ²FBGUN Fiziko-tehniceskij institut imeni A F Ioffe Rossijskoj akademii nauk, Saint Petersburg, Russia
• ³International School for Advanced Studies (SISSA), Trieste, Italy
• ⁴Shanghai Jiaotong University School of Medicine Xinhua Hospital, Shanghai, China
• ⁵«ATG Service Gene» LLC, Saint Petersburg, Russia, Saint Petersburg, Russia

A potential analgesic medicinal substance has been discovered, the ouabain–Ca2+ chelate complex (EO). As we have found, the specific EO binding to the Na,K-ATPase (NKA) in nanomolar concentrations triggers several signaling cascades in the nociceptive neuron, two of which have been discussed elsewhere. The docking results indicate that the molecular basis for the specificity of EO– NKA binding is the formation of two intermolecular ionic bonds between the chelated Ca2+ cation and two NKA carboxylate anion, Glu116 and Glu117. The third downstream EO-triggered NKA/Src/PKA/p38 MAPK/NF-κB signaling pathway, likely, controls the GAP43 gene expression, which results in this case in the neurite-inhibiting effect at the tissue level. The strong EO analgesic effect at both the spinal and supraspinal levels has been demonstrated in the formalin test. EO is a promising candidate for the role of a novel and safe analgesic, which might be particularly effective for the treatment of the tumor-associated pain syndromes due to its possible cytostatic function.