Jin-Sung Choi1, Sulayman D Dib-Hajj, Stephen G Waxman. 1. Department of Neurology, Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA.
Abstract
BACKGROUND: Inherited erythermalgia (also termed "erythromelalgia"), characterized by episodic burning pain in the distal extremities evoked by warmth, has been causally linked with mutations of the Na(v)1.7 sodium channel, which is preferentially expressed in nociceptors. Thus far, Na(v)1.7 mutations within intracellular linker parts of the channel have been physiologically characterized. OBJECTIVE: To investigate a Na(v)1.7 erythermalgia mutation that substitutes one uncharged amino acid for another within an S4 segment. METHODS: Whole-cell patch-clamp analysis was used to study biophysical properties of wild-type and mutant (F216S) Na(v)1.7 channels in mammalian cells. RESULTS: The F216S mutation hyperpolarizes the voltage dependence of activation by 11 mV, accelerates activation, slows deactivation, and enhances the response to slow, small depolarizations. CONCLUSION: These results provide a physiologic basis for the linkage to erythermalgia of an Na(v)1.7 mutation that substitutes one uncharged residue for another within an S4 segment of the channel. These changes should increase excitability of nociceptive dorsal root ganglion neurons in which the mutant channel is present, thus contributing to pain.
BACKGROUND: Inherited erythermalgia (also termed "erythromelalgia"), characterized by episodic burning pain in the distal extremities evoked by warmth, has been causally linked with mutations of the Na(v)1.7 sodium channel, which is preferentially expressed in nociceptors. Thus far, Na(v)1.7 mutations within intracellular linker parts of the channel have been physiologically characterized. OBJECTIVE: To investigate a Na(v)1.7 erythermalgia mutation that substitutes one uncharged amino acid for another within an S4 segment. METHODS: Whole-cell patch-clamp analysis was used to study biophysical properties of wild-type and mutant (F216S) Na(v)1.7 channels in mammalian cells. RESULTS: The F216S mutation hyperpolarizes the voltage dependence of activation by 11 mV, accelerates activation, slows deactivation, and enhances the response to slow, small depolarizations. CONCLUSION: These results provide a physiologic basis for the linkage to erythermalgia of an Na(v)1.7 mutation that substitutes one uncharged residue for another within an S4 segment of the channel. These changes should increase excitability of nociceptive dorsal root ganglion neurons in which the mutant channel is present, thus contributing to pain.
Authors: Xiaoyang Cheng; Sulayman D Dib-Hajj; Lynda Tyrrell; Dowain A Wright; Tanya Z Fischer; Stephen G Waxman Journal: Mol Pain Date: 2010-04-29 Impact factor: 3.395