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View article: Human-specific features of the cerebellum and ZP2-regulated synapse development
Human-specific features of the cerebellum and ZP2-regulated synapse development Open
Understanding the unique features of the human brain compared to non-human primates has long intrigued humankind. The cerebellum refines motor coordination and cognitive functions, contributing to the evolutionary development of human adap…
View article: Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability
Kv7-specific activators hyperpolarize resting membrane potential and modulate human iPSC-derived sensory neuron excitability Open
Chronic pain is highly prevalent and remains a significant unmet global medical need. As part of a search for modulatory genes that confer pain resilience, we have studied two family cohorts where one individual reported much less pain tha…
View article: Fibroblast growth factor homologous factor 2 attenuates excitability of DRG neurons
Fibroblast growth factor homologous factor 2 attenuates excitability of DRG neurons Open
FHF2 is known to bind to and modulate the function of Nav1.7. FHF2 expression is also reduced after nerve injury. We demonstrate that knockdown of FHF2 expression increases DRG neuronal excitability. More importantly, overexpression of FHF…
View article: Depolarizing Na<sub>V</sub> and Hyperpolarizing K<sub>V</sub> Channels Are Co-Trafficked in Sensory Neurons
Depolarizing Na<sub>V</sub> and Hyperpolarizing K<sub>V</sub> Channels Are Co-Trafficked in Sensory Neurons Open
Neuronal excitability relies on coordinated action of functionally distinction channels. Voltage-gated sodium (NaV) and potassium (KV) channels have distinct but complementary roles in firing action potentials: NaV channels provide depolar…
View article: Inhibition of sodium conductance by cannabigerol contributes to a reduction of dorsal root ganglion neuron excitability
Inhibition of sodium conductance by cannabigerol contributes to a reduction of dorsal root ganglion neuron excitability Open
Background and Purpose Cannabigerol (CBG), a non‐psychotropic phytocannabinoid and a precursor of ∆ 9 ‐tetrahydrocannabinol and cannabidiol, has been suggested to act as an analgesic. A previous study reported that CBG (10 μM) blocks volta…
View article: Lacosamide Inhibition of NaV1.7 Channels Depends on its Interaction With the Voltage Sensor Domain and the Channel Pore
Lacosamide Inhibition of NaV1.7 Channels Depends on its Interaction With the Voltage Sensor Domain and the Channel Pore Open
Lacosamide, developed as an anti-epileptic drug, has been used for the treatment of pain. Unlike typical anticonvulsants and local anesthetics which enhance fast-inactivation and bind within the pore of sodium channels, lacosamide enhances…
View article: Inhibition of sodium conductance by cannabigerol contributes to a reduction of neuronal dorsal root ganglion excitability
Inhibition of sodium conductance by cannabigerol contributes to a reduction of neuronal dorsal root ganglion excitability Open
Cannabigerol (CBG), a non-psychotropic phytocannabinoid, is a precursor for cannabis derivatives, Δ9-tetrahydrocannabinol and cannabidiol (CBD). Like CBD, CBG has been suggested as an analgesic. A previous study reported CBG (10 μM) blocks…
View article: <i>KCNQ</i> variants and pain modulation: a missense variant in Kv7.3 contributes to pain resilience
<i>KCNQ</i> variants and pain modulation: a missense variant in Kv7.3 contributes to pain resilience Open
There is a pressing need for understanding of factors that confer resilience to pain. Gain-of-function mutations in sodium channel Nav1.7 produce hyperexcitability of dorsal root ganglion neurons underlying inherited erythromelalgia, a hum…
View article: Two independent mouse lines carrying the Nav1.7 I228M gain-of-function variant display dorsal root ganglion neuron hyperexcitability but a minimal pain phenotype
Two independent mouse lines carrying the Nav1.7 I228M gain-of-function variant display dorsal root ganglion neuron hyperexcitability but a minimal pain phenotype Open
Small-fiber neuropathy (SFN), characterized by distal unmyelinated or thinly myelinated fiber loss, produces a combination of sensory dysfunction and neuropathic pain. Gain-of-function variants in the sodium channel Na v 1.7 that produce d…
View article: Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy
Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy Open
Small fibre neuropathy is a common pain disorder, which in many cases fails to respond to treatment with existing medications. Gain-of-function mutations of voltage-gated sodium channel Nav1.7 underlie dorsal root ganglion neuronal hyperex…
View article: A 49-residue sequence motif in the C terminus of Nav1.9 regulates trafficking of the channel to the plasma membrane
A 49-residue sequence motif in the C terminus of Nav1.9 regulates trafficking of the channel to the plasma membrane Open
Genetic and functional studies have confirmed an important role for the voltage-gated sodium channel Nav1.9 in human pain disorders. However, low functional expression of Nav1.9 in heterologous systems (e.g. in human embryonic kidney 293 (…
View article: A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain
A Novel Gain-of-Function Nav1.9 Mutation in a Child With Episodic Pain Open
Voltage-gated sodium channel Nav1.9 is a threshold channel that regulates action potential firing. Nav1.9 is preferentially expressed in myenteric neurons, and small-diameter dorsal root ganglion (DRG) and trigeminal ganglion neurons inclu…
View article: A gain-of-function sodium channel <b>β</b>2-subunit mutation in painful diabetic neuropathy
A gain-of-function sodium channel <b>β</b>2-subunit mutation in painful diabetic neuropathy Open
Diabetes mellitus is a global challenge with many diverse health sequelae, of which diabetic peripheral neuropathy is one of the most common. A substantial number of patients with diabetic peripheral neuropathy develop chronic pain, but th…
View article: Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation
Atypical changes in DRG neuron excitability and complex pain phenotype associated with a Nav1.7 mutation that massively hyperpolarizes activation Open
Sodium channel Na v 1.7 plays a central role in pain-signaling: gain-of-function Na v 1.7 mutations usually cause severe pain and loss-of-function mutations produce insensitivity to pain. The Na v 1.7 I234T gain-of-function mutation, howev…
View article: A novel gain-of-function Na<sub>v</sub>1.7 mutation in a carbamazepine-responsive patient with adult-onset painful peripheral neuropathy
A novel gain-of-function Na<sub>v</sub>1.7 mutation in a carbamazepine-responsive patient with adult-onset painful peripheral neuropathy Open
Voltage-gated sodium channel Na v 1.7 is a threshold channel in peripheral dorsal root ganglion (DRG), trigeminal ganglion, and sympathetic ganglion neurons. Gain-of-function mutations in Na v 1.7 have been shown to increase excitability i…
View article: Nonlinear effects of hyperpolarizing shifts in activation of mutant Na<sub>v</sub>1.7 channels on resting membrane potential
Nonlinear effects of hyperpolarizing shifts in activation of mutant Na<sub>v</sub>1.7 channels on resting membrane potential Open
The Na v 1.7 sodium channel is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons. Gain-of-function mutations that cause the painful disorder inherited erythromelalgia (IEM) shift channel activation…
View article: Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli
Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli Open
Inherited erythromelalgia (IEM), a severe pain syndrome characterized by episodes of intense burning pain triggered by warmth, is caused by mutations in sodium channel Nav1.7, which are preferentially expressed in sensory and sympathetic n…
View article: Pharmacotherapy for Pain in a Family With Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling
Pharmacotherapy for Pain in a Family With Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling Open
Our results demonstrate that pharmacotherapy guided by genomic analysis, molecular modeling, and functional profiling can attenuate neuropathic pain in patients carrying the S241T mutation.
View article: Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release
Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release Open
Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective in…