Nav1.7
Encyclopedia
Nav1.7 is a sodium ion channel
that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of neuron
s, the nociceptive neurons at dorsal root ganglion
(DRG) and trigeminal ganglion
, and sympathetic ganglion neurons, which are part of the autonomic
(involuntary) nervous system.
s and is thus important for electrical signaling by most excitable cells. Nav1.7 is present at the endings of pain-sensing nerves, the nociceptors, close to region where the impulse is initiated. Stimulation of the nociceptor nerve endings produces "generator potentials", which is small changes in the voltage across the neuronal membranes. The Nav1.7 channel amplifies these membrane depolarizations, and when the membrane potential difference reaches a specific threshold
, the neuron fires. In sensory neurons, multiple voltage-dependent sodium currents can be differentiated by their voltage dependence and by sensitivity to the voltage-gated sodium-channel blocker tetrodotoxin
. The Nav1.7 channel produces a rapidly activating and inactivating current which is sensitive to level of tetrodotoxin
. Nav1.7 is important in early phases of neuronal electrogenesis. Nav1.7 is described by slow transition of the channel into an inactive state when it is depolarized, even to a minor degree. This property that allows these channels to remain available for activation with even small or slowly developing depolarizations. Stimulation of the nociceptor nerve endings produces "generator potentials", which is small changes in the voltage across the neuronal membranes. This brings neurons to certain voltage that stimulate Nav1.8
, which has a more depolarized activation threshold that produces most of the transmembrane current responsible for the depolarizing phase of action potentials.
is originated from the observation that DRG neurons in animal models in inflammatory pain showed increase response to Nav1.7. Also knockout mice that lack Nav1.7 in nociceptors showed reduced response to inflammatory pain. However, neuropathic pain
(chronic pain resulting from injury to the nervous system) remained intact. These results are consistent with an important role of Nav1.7 in setting the inflammatory pain threshold. To observe the role of Nav1.7 in relation to other sodium channels expressed in peripheral sensory neurons, the researchers created mice deficient in both Nav1.7 and Nav1.8 channels. Mice deficient in Nav1.8 had deficits in sensing inflammatory pain (initiated by tissue damage/inflammation) and visceral pain (initiated by damage or injury to internal organs) but not neuropathic pain
. The thermal pain threshold in mice deficient in both Nav1.7 and Nav1.8 mice was twice that of mice lacking only Nav1.7. The result clearly implicate Nav1.7 as a major sodium channel in peripheral nociception and suggest a functional link to Nav1.8.
(PE), an autosomal dominant, inherited disorder which is characterized by attacks or episodes of symmetrical burning pain
of the feet, lower legs, and sometimes hands, elevated skin temperature of affected areas, and reddened extremities. The mutation causes excessive channel activity which suggests that Nav1.7 sets the gain on pain signaling in humans. It was observed that a missense mutation
in the SCN9A gene affected conserved residues in the pore-forming α subunit of the Nav1.7 channel. Many studies have found a dozen SCN9A mutations in multiple families as causing erythromelagia. All of the observed erythromelalgia
mutations that are observed are missense mutations that change important and highly conserved amino acid residues of the Nav1.7 protein. The majority of mutations that cause PE are located in cytoplasmic linkers of the Nav1.7 channel, however some mutations are present in transmembrane domains of the channel. The PE mutations cause a hyperpolarizing shift in the voltage dependence of channel activation, which allows the channel to be activated by smaller than normal depolarizations, thus enhancing the activity of Nav1.7. Moreover, the majority of the PE mutations also slow deactivation, thus keeping the channel open longer once it is activated. In addition, in response to a slow, depolarizing stimulus, most mutant channels will generate a larger than normal sodium current. Each of these alterations in activation and deactivation can contribute to the hyperexcitability of pain-signaling DRG
neurons expressing these mutant channels, thus causing extreme sensitivity to pain hyperalgesia
. While the expression of PE Nav1.7 mutations produces hyperexcitability in DRG neurons, studies on cultured rat in sympathetic ganglion neurons indicate that expression of these same PE mutations results in reduction of excitability of these cells. This occurs because Nav1.8 channels, which are selectively expressed in addition to Nav1.7 in DRG neurons, are not present within sympathetic ganglion neurons. Thus lack of Nav1.7 results in inactivation of the sodium channels results in reduced excitability. Thus physiological interaction of Nav1.7 and Nav1.8 can explain the reason that PE presents with pain due to hyperexcitability of nociceptors and with sympathetic dysfunction that is most likely due to hypoexcitability of sympathetic ganglion neurons.
Recent studies have associated a defect in SCN9A with congenital insensitivity to pain
.
have painless injuries beginning in infancy but otherwise normal sensory responses upon examination. Patients frequently have bruises and cuts, and are often only diagnosed because of limping or lack of use of a limb
. Individuals have been reported to be able to walk over burning coals and to insert knives and drive spikes through their arms. It has been observed that the insensitivity to pain does not appear to be due to axonal degeneration.
A mutation that caused loss of Nav1.7 function has been detected in three consanguineous families from northern Pakistan. All mutation observed were nonsense mutation
with majority of affected patients having homozygous mutation in the SCN9A gene. Their observation linked loss of Nav1.7 function with incapability to experience pain. The result was in contrast with the genetic basis of primary erythromelalgia
in which the disorder results from gain-of-function mutations.
Sodium ion channel
Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions through a cell's plasma membrane. They are classified according to the trigger that opens the channel for such ions, i.e...
that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s, the nociceptive neurons at dorsal root ganglion
Dorsal root ganglion
In anatomy and neuroscience, a dorsal root ganglion is a nodule on a dorsal root that contains cell bodies of neurons in afferent spinal nerves.-Unique unipolar structure:...
(DRG) and trigeminal ganglion
Trigeminal ganglion
The trigeminal ganglion is a sensory ganglion of the trigeminal nerve that occupies a cavity in the dura mater, covering the trigeminal impression near the apex of the petrous part of the temporal bone.-Relations:It is somewhat crescentic in shape, with its convexity...
, and sympathetic ganglion neurons, which are part of the autonomic
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
(involuntary) nervous system.
Function
Nav1.7 is a voltage-gated sodium channel and plays a critical role in the generation and conduction of action potentialAction potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
s and is thus important for electrical signaling by most excitable cells. Nav1.7 is present at the endings of pain-sensing nerves, the nociceptors, close to region where the impulse is initiated. Stimulation of the nociceptor nerve endings produces "generator potentials", which is small changes in the voltage across the neuronal membranes. The Nav1.7 channel amplifies these membrane depolarizations, and when the membrane potential difference reaches a specific threshold
Threshold potential
The threshold potential is the membrane potential to which a membrane must be depolarized to initiate an action potential.It often can be between −40 and -55 mV, but it can vary based upon several factors...
, the neuron fires. In sensory neurons, multiple voltage-dependent sodium currents can be differentiated by their voltage dependence and by sensitivity to the voltage-gated sodium-channel blocker tetrodotoxin
Tetrodotoxin
Tetrodotoxin, also known as "tetrodox" and frequently abbreviated as TTX, sometimes colloquially referred to as "zombie powder" by those who practice Vodou, is a potent neurotoxin with no known antidote. There have been successful tests of a possible antidote in mice, but further tests must be...
. The Nav1.7 channel produces a rapidly activating and inactivating current which is sensitive to level of tetrodotoxin
Tetrodotoxin
Tetrodotoxin, also known as "tetrodox" and frequently abbreviated as TTX, sometimes colloquially referred to as "zombie powder" by those who practice Vodou, is a potent neurotoxin with no known antidote. There have been successful tests of a possible antidote in mice, but further tests must be...
. Nav1.7 is important in early phases of neuronal electrogenesis. Nav1.7 is described by slow transition of the channel into an inactive state when it is depolarized, even to a minor degree. This property that allows these channels to remain available for activation with even small or slowly developing depolarizations. Stimulation of the nociceptor nerve endings produces "generator potentials", which is small changes in the voltage across the neuronal membranes. This brings neurons to certain voltage that stimulate Nav1.8
SCN10A
Sodium channel, voltage gated, type X, alpha subunit also known as SCN10A or Nav1.8 is a protein which in humans is encoded by the SCN10A gene.Nav1.8 is a sodium channel subunit.-Function:...
, which has a more depolarized activation threshold that produces most of the transmembrane current responsible for the depolarizing phase of action potentials.
Animal studies
Clues that Nav1.7 is involved in painPain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
is originated from the observation that DRG neurons in animal models in inflammatory pain showed increase response to Nav1.7. Also knockout mice that lack Nav1.7 in nociceptors showed reduced response to inflammatory pain. However, neuropathic pain
Neuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
(chronic pain resulting from injury to the nervous system) remained intact. These results are consistent with an important role of Nav1.7 in setting the inflammatory pain threshold. To observe the role of Nav1.7 in relation to other sodium channels expressed in peripheral sensory neurons, the researchers created mice deficient in both Nav1.7 and Nav1.8 channels. Mice deficient in Nav1.8 had deficits in sensing inflammatory pain (initiated by tissue damage/inflammation) and visceral pain (initiated by damage or injury to internal organs) but not neuropathic pain
Neuropathic pain
Neuropathic pain results from lesions or diseases affecting the somatosensory system. It may be associated with abnormal sensations called dysesthesia, which occur spontaneously and allodynia that occurs in response to external stimuli. Neuropathic pain may have continuous and/or episodic ...
. The thermal pain threshold in mice deficient in both Nav1.7 and Nav1.8 mice was twice that of mice lacking only Nav1.7. The result clearly implicate Nav1.7 as a major sodium channel in peripheral nociception and suggest a functional link to Nav1.8.
Primary erythromelalgia
Mutation in Nav1.7 may result in primary erythromelalgiaErythromelalgia
Erythromelalgia, also known as Mitchell's disease , acromelalgia, red neuralgia, or erythermalgia, is a rare neurovascular peripheral pain disorder in which blood vessels, usually in the lower extremities , are episodically blocked , then become hyperemic and inflamed...
(PE), an autosomal dominant, inherited disorder which is characterized by attacks or episodes of symmetrical burning pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
of the feet, lower legs, and sometimes hands, elevated skin temperature of affected areas, and reddened extremities. The mutation causes excessive channel activity which suggests that Nav1.7 sets the gain on pain signaling in humans. It was observed that a missense mutation
Missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide is changed, resulting in a codon that codes for a different amino acid . This can render the resulting protein nonfunctional...
in the SCN9A gene affected conserved residues in the pore-forming α subunit of the Nav1.7 channel. Many studies have found a dozen SCN9A mutations in multiple families as causing erythromelagia. All of the observed erythromelalgia
Erythromelalgia
Erythromelalgia, also known as Mitchell's disease , acromelalgia, red neuralgia, or erythermalgia, is a rare neurovascular peripheral pain disorder in which blood vessels, usually in the lower extremities , are episodically blocked , then become hyperemic and inflamed...
mutations that are observed are missense mutations that change important and highly conserved amino acid residues of the Nav1.7 protein. The majority of mutations that cause PE are located in cytoplasmic linkers of the Nav1.7 channel, however some mutations are present in transmembrane domains of the channel. The PE mutations cause a hyperpolarizing shift in the voltage dependence of channel activation, which allows the channel to be activated by smaller than normal depolarizations, thus enhancing the activity of Nav1.7. Moreover, the majority of the PE mutations also slow deactivation, thus keeping the channel open longer once it is activated. In addition, in response to a slow, depolarizing stimulus, most mutant channels will generate a larger than normal sodium current. Each of these alterations in activation and deactivation can contribute to the hyperexcitability of pain-signaling DRG
Dorsal root ganglion
In anatomy and neuroscience, a dorsal root ganglion is a nodule on a dorsal root that contains cell bodies of neurons in afferent spinal nerves.-Unique unipolar structure:...
neurons expressing these mutant channels, thus causing extreme sensitivity to pain hyperalgesia
Hyperalgesia
Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...
. While the expression of PE Nav1.7 mutations produces hyperexcitability in DRG neurons, studies on cultured rat in sympathetic ganglion neurons indicate that expression of these same PE mutations results in reduction of excitability of these cells. This occurs because Nav1.8 channels, which are selectively expressed in addition to Nav1.7 in DRG neurons, are not present within sympathetic ganglion neurons. Thus lack of Nav1.7 results in inactivation of the sodium channels results in reduced excitability. Thus physiological interaction of Nav1.7 and Nav1.8 can explain the reason that PE presents with pain due to hyperexcitability of nociceptors and with sympathetic dysfunction that is most likely due to hypoexcitability of sympathetic ganglion neurons.
Recent studies have associated a defect in SCN9A with congenital insensitivity to pain
Congenital insensitivity to pain
Congenital insensitivity to pain , also known as congenital analgesia, is one or more rare conditions where a person cannot feel physical pain...
.
Insensitivity to pain
Individuals with congenital insensitivity to painCongenital insensitivity to pain
Congenital insensitivity to pain , also known as congenital analgesia, is one or more rare conditions where a person cannot feel physical pain...
have painless injuries beginning in infancy but otherwise normal sensory responses upon examination. Patients frequently have bruises and cuts, and are often only diagnosed because of limping or lack of use of a limb
Limb (anatomy)
A limb is a jointed, or prehensile , appendage of the human or other animal body....
. Individuals have been reported to be able to walk over burning coals and to insert knives and drive spikes through their arms. It has been observed that the insensitivity to pain does not appear to be due to axonal degeneration.
A mutation that caused loss of Nav1.7 function has been detected in three consanguineous families from northern Pakistan. All mutation observed were nonsense mutation
Nonsense mutation
In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a premature stop codon, or a nonsense codon in the transcribed mRNA, and in a truncated, incomplete, and usually nonfunctional protein product. It differs from a missense mutation, which is a point mutation...
with majority of affected patients having homozygous mutation in the SCN9A gene. Their observation linked loss of Nav1.7 function with incapability to experience pain. The result was in contrast with the genetic basis of primary erythromelalgia
Erythromelalgia
Erythromelalgia, also known as Mitchell's disease , acromelalgia, red neuralgia, or erythermalgia, is a rare neurovascular peripheral pain disorder in which blood vessels, usually in the lower extremities , are episodically blocked , then become hyperemic and inflamed...
in which the disorder results from gain-of-function mutations.