Sodium channel beta2 subunits regulate tetrodotoxin-sensitive sodium channels in small dorsal root ganglion neurons and modulate the response to pain.
Voltage-gated sodium channel (Na(v)1) beta2 subunits modulate channel gating, assembly, and cell-surface expression in CNS neurons in vitro and in vivo. beta2 expression increases in sensory neurons after nerve injury, and development of mechanical allodynia in the spared nerve injury model is attenuated in beta2-null mice. Thus, we hypothesized that beta2 modulates electrical excitability in dorsal root ganglion (DRG) neurons in vivo. We compared sodium currents (I(Na)) in small DRG neurons from beta2+/+ and beta2-/- mice to determine the effects of beta2 on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na(v)1 in vivo. Small-fast DRG neurons acutely isolated from beta2-/- mice showed significant decreases in TTX-S I(Na) compared with beta2+/+ neurons. This decrease included a 51% reduction in maximal sodium conductance with no detectable changes in the voltage dependence of activation or inactivation. TTX-S, but not TTX-R, I(Na) activation and inactivation kinetics in these cells were slower in beta2(-/-) mice compared with controls. The selective regulation of TTX-S I(Na) was supported by reductions in transcript and protein levels of TTX-S Na(v)1s, particularly Na(v)1.7. Low-threshold mechanical sensitivity was preserved in beta2-/- mice, but they were more sensitive to noxious thermal stimuli than wild type whereas their response during the late phase of the formalin test was attenuated. Our results suggest that beta2 modulates TTX-S Na(v)1 mRNA and protein expression resulting in increased TTX-S I(Na) and increases the rates of TTX-S Na(v)1 activation and inactivation in small-fast DRG neurons in vivo. TTX-R I(Na) were not significantly modulated by beta2.
Lopez-Santiago
Luis F
LF
Department of Pharmacology, University of Michigan, Ann Arbor, Michigan 48109-0632, USA.
Pertin
Marie
M
Morisod
Xavier
X
Chen
Chunling
C
Hong
Shuangsong
S
Wiley
John
J
Decosterd
Isabelle
I
Isom
Lori L
LL
D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D015222:Sodium Channels / Q000378:metabolism*; D013779:Tetrodotoxin / Q000008:administration & dosage*; D062548:Voltage-Gated Sodium Channel beta-2 Subunit
D009419:Nerve Tissue Proteins; C117620:SCN2B protein, human; D015222:Sodium Channels; D062548:Voltage-Gated Sodium Channel beta-2 Subunit; D013779:Tetrodotoxin