Real-time imaging of axonal membrane protein life cycles.

The construction of neuronal membranes is a dynamic process involving the biogenesis, vesicular packaging, transport, insertion and recycling of membrane proteins. Optical imaging is well suited for the study of protein spatial organization and transport. However, various shortcomings of existing imaging techniques have prevented the study of specific types of proteins and cellular processes.

Conserved but not critical: Trafficking and function of Na1.7 are independent of highly conserved polybasic motifs.

Non-addictive treatment of chronic pain represents a major unmet clinical need. Peripheral voltage-gated sodium (Na) channels are an attractive target for pain therapy because they initiate and propagate action potentials in primary afferents that detect and transduce noxious stimuli. Na1.

Inflammation differentially controls transport of depolarizing Nav versus hyperpolarizing Kv channels to drive rat nociceptor activity.

Inflammation causes pain by shifting the balance of ionic currents in nociceptors toward depolarization, leading to hyperexcitability. The ensemble of ion channels within the plasma membrane is regulated by processes including biogenesis, transport, and degradation. Thus, alterations in ion channel trafficking may influence excitability.

Paclitaxel effects on axonal localization and vesicular trafficking of Na1.8.

Patients treated with paclitaxel (PTX) or other antineoplastic agents can experience chemotherapy-induced peripheral neuropathy (CIPN), a debilitating side effect characterized by numbness and pain. PTX interferes with microtubule-based transport, which inhibits tumor growth cell cycle arrest but can also affect other cellular functions including trafficking of ion channels critical to transduction of stimuli by sensory neurons of the dorsal root ganglia (DRG). We examined the effects of PTX on voltage-gated sodium channel Na1.

The fates of internalized Na1.7 channels in sensory neurons: Retrograde cotransport with other ion channels, axon-specific recycling, and degradation.

Neuronal function relies on the maintenance of appropriate levels of various ion channels at the cell membrane, which is accomplished by balancing secretory, degradative, and recycling pathways. Neuronal function further depends on membrane specialization through polarized distribution of specific proteins to distinct neuronal compartments such as axons. Voltage-gated sodium channel Na1.

Lacosamide Inhibition of Na1.7 Channels Depends on its Interaction With the Voltage Sensor Domain and the Channel Pore.

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 slow-inactivation of these channels, suggesting different binding mechanisms and mode of action. It has been reported that lacosamide's effect on Na1.

variants and pain modulation: a missense variant in Kv7.3 contributes to pain resilience.

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 human genetic model of neuropathic pain.

Paclitaxel increases axonal localization and vesicular trafficking of Nav1.7.

The microtubule-stabilizing chemotherapy drug paclitaxel (PTX) causes dose-limiting chemotherapy-induced peripheral neuropathy (CIPN), which is often accompanied by pain. Among the multifaceted effects of PTX is an increased expression of sodium channel Nav1.7 in rat and human sensory neurons, enhancing their excitability.

Pharmacological characterization of a rat Nav1.7 loss-of-function model with insensitivity to pain.

Sodium channel Nav1.7, encoded by the SCN9A gene, is a well-validated target that plays a key role in controlling pain sensation. Loss-of-function mutations of Nav1.

Building sensory axons: Delivery and distribution of Na1.7 channels and effects of inflammatory mediators.

Sodium channel Na1.7 controls firing of nociceptors, and its role in human pain has been validated by genetic and functional studies. However, little is known about Na1.

The Novel Activity of Carbamazepine as an Activation Modulator Extends from Na1.7 Mutations to the Na1.8-S242T Mutant Channel from a Patient with Painful Diabetic Neuropathy.

Neuropathic pain in patients carrying sodium channel gain-of-function mutations is generally refractory to pharmacotherapy. However, we have shown that pretreatment of cells with clinically achievable concentration of carbamazepine (CBZ; 30 M) depolarizes the voltage dependence of activation in some Na1.7 mutations such as S241T, a novel CBZ mode of action of this drug.

Conditional knockout of Na1.6 in adult mice ameliorates neuropathic pain.

Voltage-gated sodium channels Na1.7, Na1.8 and Na1.

A gain-of-function mutation in Nav1.6 in a case of trigeminal neuralgia.

Idiopathic trigeminal neuralgia (TN) is a debilitating pain disorder characterized by episodic unilateral facial pain along the territory of branches of the trigeminal nerve. Human painful disorders, but not TN, have been linked to gain-of-function mutations in peripheral voltage-gated sodium channels (Na1.7, Na1.