A single sodium channel mutation produces hyper-or hypoexcitability in different types of neurons

AM Rush, SD Dib-Hajj, S Liu… - Proceedings of the …, 2006 - National Acad Sciences
AM Rush, SD Dib-Hajj, S Liu, TR Cummins, JA Black, SG Waxman
Proceedings of the National Academy of Sciences, 2006National Acad Sciences
Disease-producing mutations of ion channels are usually characterized as producing
hyperexcitability or hypoexcitability. We show here that a single mutation can produce
hyperexcitability in one neuronal cell type and hypoexcitability in another neuronal cell type.
We studied the functional effects of a mutation of sodium channel Nav1. 7 associated with a
neuropathic pain syndrome, erythermalgia, within sensory and sympathetic ganglion
neurons, two cell types where Nav1. 7 is normally expressed. Although this mutation …
Disease-producing mutations of ion channels are usually characterized as producing hyperexcitability or hypoexcitability. We show here that a single mutation can produce hyperexcitability in one neuronal cell type and hypoexcitability in another neuronal cell type. We studied the functional effects of a mutation of sodium channel Nav1.7 associated with a neuropathic pain syndrome, erythermalgia, within sensory and sympathetic ganglion neurons, two cell types where Nav1.7 is normally expressed. Although this mutation depolarizes resting membrane potential in both types of neurons, it renders sensory neurons hyperexcitable and sympathetic neurons hypoexcitable. The selective presence, in sensory but not sympathetic neurons, of the Nav1.8 channel, which remains available for activation at depolarized membrane potentials, is a major determinant of these opposing effects. These results provide a molecular basis for the sympathetic dysfunction that has been observed in erythermalgia. Moreover, these findings show that a single ion channel mutation can produce opposing phenotypes (hyperexcitability or hypoexcitability) in the different cell types in which the channel is expressed.
National Acad Sciences