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
Michael L
ML
Department of Psychology and Centre for Research on Pain, McGill University, 1205 Dr. Penfield Ave., Montreal, Que., Canada H3A 1B1 Department of Neurology and Neurosurgery, Montreal Neurological Institute, and Centre for Research on Pain, McGill University, Montreal, Que., Canada H3A 2B4 Department of Anesthesiology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA Department of Genetics and Genomics, Roche Palo Alto, Palo Alto, CA 94304, USA Integrated DNA Technologies Inc., Coralville, IA 52241, USA Department of Anesthesiology, Stanford University, Palo Alto, CA 94304, USA Department of Anesthesia, Stanford University, Stanford, CA 94305, USA.
Mo
Gary
G
Smith
Shad B
SB
Sotocinal
Susana G
SG
Ritchie
Jennifer
J
Austin
Jean-Sebastien
JS
Melmed
Kara
K
Schorscher-Petcu
Ara
A
Laferriere
Audrey C
AC
Lee
Tae Hoon
TH
Romanovsky
Dmitry
D
Liao
Guochun
G
Behlke
Mark A
MA
Clark
David J
DJ
Peltz
Gary
G
Séguéla
Philippe
P
Dobretsov
Maxim
M
Mogil
Jeffrey S
JS
D000818:Animals; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005727:Ganglia, Spinal / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009619:Nociceptors / Q000201:enzymology*; D010146:Pain / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology*; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering; D011984:Sensory Receptor Cells / Q000201:enzymology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity
C519304:ATP1B3 protein, human; C543873:Atp1b3 protein, mouse; D021122:Protein Subunits; D034741:RNA, Small Interfering; D000254:Sodium-Potassium-Exchanging ATPase