Electrophysiological Properties of Mutant Nav1.7 Sodium Channels in a Painful Inherited Neuropathy

Although the physiological basis of erythermalgia, an autosomal dominant painful neuropathy characterized by redness of the skin and intermittent burning sensation of extremities, is not known, two mutations of Nav1.7, a sodium channel that produces a tetrodotoxin-sensitive, fast-inactivating current that is preferentially expressed in dorsal root ganglia (DRG) and sympathetic ganglia neurons, have recently been identified in patients with primary erythermalgia. Nav1.7 is preferentially expressed in small-diameter DRG neurons, most of which are nociceptors, and is characterized by slow recovery from inactivation and by slow closed-state inactivation that results in relatively large responses to small, subthreshold depolarizations. Here we show that these mutations in Nav1.7 produce a hyperpolarizing shift in activation and slow deactivation. We also show that these mutations cause an increase in amplitude of the current produced by Nav1.7 in response to slow, small depolarizations. These observations provide the first demonstration of altered sodium channel function associated with an inherited painful neuropathy and suggest that these physiological changes, which confer hyperexcitability on peripheral sensory and sympathetic neurons, contribute to symptom production in hereditary erythermalgia.

[1]  L. Djouhri,et al.  Sensory and electrophysiological properties of guinea‐pig sensory neurones expressing Nav 1.7 (PN1) Na+ channel α subunit protein , 2003, The Journal of physiology.

[2]  N. Klugbauer,et al.  Structure and functional expression of a new member of the tetrodotoxin‐sensitive voltage‐activated sodium channel family from human neuroendocrine cells. , 1995, The EMBO journal.

[3]  S. Dib-Hajj,et al.  Spinal sensory neurons express multiple sodium channel alpha-subunit mRNAs. , 1996, Brain research. Molecular brain research.

[4]  S. Waxman,et al.  Contribution of Na(v)1.8 sodium channels to action potential electrogenesis in DRG neurons. , 2001, Journal of neurophysiology.

[5]  S. Dib-Hajj,et al.  Sodium channels and their genes: dynamic expression in the normal nervous system, dysregulation in disease states 1 1 Published on the World Wide Web on 15 August 2000. , 2000, Brain Research.

[6]  P. Ruben,et al.  A defect in skeletal muscle sodium channel deactivation exacerbates hyperexcitability in human paramyotonia congenita , 1998, The Journal of physiology.

[7]  S. Waxman,et al.  Slow Closed-State Inactivation: A Novel Mechanism Underlying Ramp Currents in Cells Expressing the hNE/PN1 Sodium Channel , 1998, The Journal of Neuroscience.

[8]  R Ottman,et al.  Identification of epilepsy genes in human and mouse. , 2001, Annual review of genetics.

[9]  M. Devor,et al.  Hyperexcitability at sites of nerve injury depends on voltage-sensitive Na+ channels. , 1994, Journal of neurophysiology.

[10]  Masaki Tanaka,et al.  Changes in the expression of tetrodotoxin-sensitive sodium channels within dorsal root ganglia neurons in inflammatory pain , 2004, Pain.

[11]  S. Waxman,et al.  Three types of sodium channels in adult rat dorsal root ganglion neurons , 1992, Brain Research.

[12]  R. Eglen,et al.  Structure and Function of a Novel Voltage-gated, Tetrodotoxin-resistant Sodium Channel Specific to Sensory Neurons (*) , 1996, The Journal of Biological Chemistry.

[13]  B. Ding,et al.  Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia , 2004, Journal of Medical Genetics.

[14]  P. Grafe,et al.  Adynamia episodica hereditaria with myotonia: A non‐inactivating sodium current and the effect of extracellular pH , 1987, Muscle & nerve.

[15]  S. Dib-Hajj,et al.  Spinal sensory neurons express multiple sodium channel α-subunit mRNAs , 1996 .

[16]  A. George,et al.  Functional expression of the Ile693Thr Na+ channel mutation associated with paramyotonia congenita in a human cell line , 1998, The Journal of physiology.

[17]  S. Waxman,et al.  Altered Sodium Channel Expression in Second-Order Spinal Sensory Neurons Contributes to Pain after Peripheral Nerve Injury , 2004, The Journal of Neuroscience.

[18]  S. Cannon,et al.  Defective slow inactivation of sodium channels contributes to familial periodic paralysis , 1999, Neurology.

[19]  F Bezanilla,et al.  A sodium channel gating model based on single channel, macroscopic ionic, and gating currents in the squid giant axon. , 1991, Biophysical journal.

[20]  R. Ruff Slow Na+ channel inactivation must be disrupted to evoke prolonged depolarization-induced paralysis. , 1994, Biophysical journal.

[21]  A. L. Goldin,et al.  Resurgence of sodium channel research. , 2001, Annual review of physiology.

[22]  K. Wong,et al.  A Novel Tetrodotoxin-sensitive, Voltage-gated Sodium Channel Expressed in Rat and Human Dorsal Root Ganglia* , 1997, The Journal of Biological Chemistry.

[23]  L. Sivilotti,et al.  A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons , 1996, Nature.

[24]  L. Djouhri,et al.  The TTX‐Resistant Sodium Channel Nav1.8 (SNS/PN3): Expression and Correlation with Membrane Properties in Rat Nociceptive Primary Afferent Neurons , 2003, The Journal of physiology.

[25]  S. Lawson,et al.  Electrical properties of rat dorsal root ganglion neurones with different peripheral nerve conduction velocities. , 1985, The Journal of physiology.

[26]  S. Dib-Hajj,et al.  NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  S. Bendahhou,et al.  Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5 , 2002, Neurology.

[28]  C. Bountra,et al.  Two sodium channels contribute to the TTX-R sodium current in primary sensory neurons , 1998, Nature Neuroscience.

[29]  S. Cannon An expanding view for the molecular basis of familial periodic paralysis , 2002, Neuromuscular Disorders.

[30]  Y. H. Chen,et al.  Upregulation of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons. , 1999, Journal of neurophysiology.

[31]  E. Stevens,et al.  beta3, a novel auxiliary subunit for the voltage-gated sodium channel, is expressed preferentially in sensory neurons and is upregulated in the chronic constriction injury model of neuropathic pain. , 2000, European Journal of Neuroscience.

[32]  P. V. van Genderen,et al.  Hereditary erythermalgia and acquired erythromelalgia. , 1993, American journal of medical genetics.

[33]  S. Waxman,et al.  Downregulation of Tetrodotoxin-Resistant Sodium Currents and Upregulation of a Rapidly Repriming Tetrodotoxin-Sensitive Sodium Current in Small Spinal Sensory Neurons after Nerve Injury , 1997, The Journal of Neuroscience.

[34]  S. Halegoua,et al.  Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  M. Sanguinetti,et al.  Molecular and Cellular Mechanisms of Cardiac Arrhythmias , 2001, Cell.

[36]  A. George,et al.  Molecular Basis of an Inherited Epilepsy , 2002, Neuron.

[37]  S. Dib-Hajj,et al.  Distinct repriming and closed‐state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons , 2003, The Journal of physiology.

[38]  F. Sigworth,et al.  Functional consequences of a Na+ channel mutation causing hyperkalemic periodic paralysis , 1993, Neuron.

[39]  R. Layzer Hot Feet: Erythromelalgia and Related Disorders , 2001, Journal of child neurology.

[40]  R. L. Kirby,et al.  The primary erythermalgia-susceptibility gene is located on chromosome 2q31-32. , 2001, American journal of human genetics.

[41]  S G Waxman,et al.  A Novel Persistent Tetrodotoxin-Resistant Sodium Current In SNS-Null And Wild-Type Small Primary Sensory Neurons , 1999, The Journal of Neuroscience.

[42]  E. Stevens,et al.  β3, a novel auxiliary subunit for the voltage‐gated sodium channel, is expressed preferentially in sensory neurons and is upregulated in the chronic constriction injury model of neuropathic pain , 2000 .