Interplay of Nav1.8 and Nav1.7 channels drives neuronal hyperexcitability in neuropathic pain.

J Gen Physiol

Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT, USA.

Published: November 2024

AI Article Synopsis

  • This study investigates how voltage-gated sodium channels Nav1.7 and Nav1.8 work together in dorsal root ganglion (DRG) neurons, particularly focusing on the impact of a mutation in Nav1.7 associated with neuropathic pain known as inherited erythromelalgia (IEM).
  • Researchers found that Nav1.8 significantly increases the likelihood of action potential (AP) generation near the voltage threshold, outperforming Nav1.7 in terms of channel open-probability at -21.9 mV by nine times.
  • Reducing Nav1.8 current by 25-50% can decrease the excitability of DRG neurons with the Nav1.7

Article Abstract

While voltage-gated sodium channels Nav1.7 and Nav1.8 both contribute to electrogenesis in dorsal root ganglion (DRG) neurons, details of their interactions have remained unexplored. Here, we studied the functional contribution of Nav1.8 in DRG neurons using a dynamic clamp to express Nav1.7L848H, a gain-of-function Nav1.7 mutation that causes inherited erythromelalgia (IEM), a human genetic model of neuropathic pain, and demonstrate a profound functional interaction of Nav1.8 with Nav1.7 close to the threshold for AP generation. At the voltage threshold of -21.9 mV, we observed that Nav1.8 channel open-probability exceeded Nav1.7WT channel open-probability ninefold. Using a kinetic model of Nav1.8, we showed that a reduction of Nav1.8 current by even 25-50% increases rheobase and reduces firing probability in small DRG neurons expressing Nav1.7L848H. Nav1.8 subtraction also reduces the amplitudes of subthreshold membrane potential oscillations in these cells. Our results show that within DRG neurons that express peripheral sodium channel Nav1.7, the Nav1.8 channel amplifies excitability at a broad range of membrane voltages with a predominant effect close to the AP voltage threshold, while Nav1.7 plays a major role at voltages closer to resting membrane potential. Our data show that dynamic-clamp reduction of Nav1.8 conductance by 25-50% can reverse hyperexcitability of DRG neurons expressing a gain-of-function Nav1.7 mutation that causes pain in humans and suggests, more generally, that full inhibition of Nav1.8 may not be required for relief of pain due to DRG neuron hyperexcitability.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465073PMC
http://dx.doi.org/10.1085/jgp.202413596DOI Listing

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