The beta3 subunit of the Na+,K+-ATPase mediates variable nociceptive sensitivity in the formalin test.
It is widely appreciated that there is significant inter-individual variability in pain sensitivity, yet only a handful of contributing genetic variants have been identified. Computational genetic mapping and quantitative trait locus analysis suggested that variation within the gene coding for the beta3 subunit of the Na+,K+-ATPase pump (Atp1b3) contributes to inter-strain differences in the early phase formalin pain behavior. Significant strain differences in Atp1b3 gene expression, beta3 protein expression, and biophysical properties of the Na+,K+ pump in dorsal root ganglia neurons from resistant (A/J) and sensitive (C57BL/6J) mouse strains supported the genetic prediction. Furthermore, in vivo siRNA knockdown of the beta3 subunit produced strain-specific changes in the early phase pain response, completely rescuing the strain difference. These findings indicate that the beta3 subunit of the Na+,K+-ATPase is a novel determinant of nociceptive sensitivity and further supports the notion that pain variability genes can have very selective effects on individual pain modalities.
LaCroix-Fralish, ML; Mo, G; Smith, SB; Sotocinal, SG; Ritchie, J; Austin, J-S; Melmed, K; Schorscher-Petcu, A; Laferriere, AC; Lee, TH; Romanovsky, D; Liao, G; Behlke, MA; Clark, DJ; Peltz, G; Séguéla, P; Dobretsov, M; Mogil, JS
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