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Last update 08 May 2025

SCN4A

Last update 08 May 2025

Basic Info

Synonyms

HYKPP, HYPP, Nav1.4

+ [10]

Introduction

Pore-forming subunit of Nav1.4, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient. The influx of Na+ ions provokes membrane depolarization, initiating the propagation of electrical signals throughout cells and tissues (PubMed:12766226, PubMed:15318338, PubMed:16890191, PubMed:17898326, PubMed:18690054, PubMed:19347921, PubMed:25707578, PubMed:26659129, PubMed:26700687, PubMed:29992740, PubMed:30190309). Highly expressed in skeletal muscles, Nav1.4 generates the action potential crucial for muscle contraction (PubMed:16890191, PubMed:19347921, PubMed:25707578, PubMed:26659129, PubMed:26700687).

Drugs associated with SCN4A

WO2022120215

Patent Mining

Target

SCN4A

Mechanism-

Active Org.

The Johns Hopkins University

Originator Org.

The Johns Hopkins University

Active Indication

Congenital Disorders [+3]

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Neosaxitoxin

Target

SCN4A

Mechanism

SCN4A blockers

Active Org.-

Originator Org.

Grunenthal SA

Active Indication-

Inactive Indication

Anesthesia

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

ST-410

Target

SCN4A

Mechanism

SCN4A blockers

Active Org.-

Originator Org.

SiteOne Therapeutics, Inc.

Active Indication-

Inactive Indication

Pain

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with SCN4A

NCT03399435

/ TerminatedPhase 1

An Exploratory Phase I Randomized, Single-site, Double-blind, Active-controlled, Parallel-group, Single-administration, Dose-escalation Trial to Investigate the Safety and Tolerability of Neosaxitoxin Alone and in Combination With Bupivacaine (With and Without Epinephrine), in Perineural Administrations for Brachial Plexus Blockade in Healthy Subjects

Neosaxitoxin is a new compound that is in clinical development as local anesthetic for surgical anesthesia and postoperative analgesia.
The primary objective of this study is to evaluate the systemic and local safety and tolerability of ascending doses of neosaxitoxin alone and in combination with fixed doses of bupivacaine (with and without epinephrine), following brachial plexus blockade in healthy male subjects.
Secondary objectives:
Evaluate the pharmacodynamics (PD) of ascending doses of neosaxitoxin, alone and in combination with fixed doses of bupivacaine (with and without epinephrine), following brachial plexus blockade.
Characterize the pharmacokinetics (PK) of neosaxitoxin and bupivacaine after brachial plexus blockade with neosaxitoxin alone or different drug combinations: neosaxitoxin and epinephrine, neosaxitoxin and bupivacaine, or neosaxitoxin and bupivacaine and epinephrine.

Start Date30 Jan 2018

Sponsor / Collaborator

Grünenthal GmbH

NCT01786655

/ CompletedPhase 1IIT

Neosaxitoxin (NeoSTX) Alone and in Combination With Bupivacaine as Prolonged Duration Local Anesthetics: A Phase I Investigator-initiated Dose Escalation Study

The primary aim of this Phase 1 study is to evaluate the systemic safety of a novel prolonged-duration local anesthetic, Neosaxitoxin (NeoSTX), given by subcutaneous injection in combination with the commonly used local anesthetic, bupivacaine, and epinephrine.
The investigators hypothesize that a "minimal adverse effect threshold" NeoSTX dose for subcutaneous administration in combination with bupivacaine 0.2% and epinephrine 5mcg/ml respectively, can be defined for awake, young adult healthy volunteer subjects. At the same time, the pharmacokinetics of NeoSTX when delivered subcutaneously will be determined.

Start Date01 May 2013

Sponsor / Collaborator

The Children's Hospital Corp.

NCT00273065

/ CompletedPhase 1IIT

Phase 1 Study of Local Infiltration of Neosaxitoxin as a Local Anesthetic

The purpose of this study is to evaluate the local anesthetic properties of neosaxitoxin in humans

Start Date01 May 2005

Sponsor / Collaborator

University of Chile

100 Clinical Results associated with SCN4A

100 Translational Medicine associated with SCN4A

0 Patents (Medical) associated with SCN4A

709

Literatures (Medical) associated with SCN4A

01 Jun 2025·European Journal of Pharmacology

SGLT2 inhibitor dapagliflozin mitigates skeletal muscle pathology by modulating key proteins involved in glucose and ion homeostasis in an animal model of heart failure

Article

Author: De Luca, Annamaria ; Conte, Elena ; Berrino, Liberato ; Mele, Elena ; Lanza, Martina ; De Angelis, Antonella ; Cappetta, Donato ; Boccanegra, Brigida ; Urbanek, Konrad ; Dinoi, Giorgia ; Riemma, Maria Antonietta ; Liantonio, Antonella ; Imbrici, Paola

Heart failure (HF) is a syndrome characterized by dyspnoea, fatigue and exercise intolerance. Among non-cardiac comorbidities which often accompany HF, skeletal muscle abnormalities impact patients' daily activities and quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promise in improving clinical outcomes and enhancing physical performance in HF patients, although their mechanism of action remains unclear. In this context, altered muscle ions and glucose homeostasis may contribute to HF-related muscle changes and serve as indirect targets for SGLT2i effects. To explore this further, we used Dahl salt-sensitive rats fed with a high-salt diet for five weeks and then randomized to receive dapagliflozin (HS + DAP) or vehicle (HS) for the following six weeks. Control animals received a low-salt diet (LS). We investigated whether variations in indexes of glucose and ions homeostasis occur in extensor digitorum longus muscle of this rodent model of HF with preserved ejection fraction and are counteracted by dapagliflozin treatment. Gene and protein expression analysis revealed altered expression of proteins involved in glucose (SGLT2, GLUT4, GPD1) and Ca²⁺ and Na ⁺ homeostasis (NCX3, Ryr1, NHE1/6, Na⁺/K⁺-ATPase, Nav1.4) in HS vs LS animals. Furthermore, HS rats showed an increased CaMKII expression in its active phosphorylated form and a change in plasma pH toward acidification. Dapagliflozin treatment counteracted the altered expression of most of the components under investigation, also promoting an amelioration of atrophy indexes and a recovery of plasma pH. Thus, skeletal muscle appears highly responsive to SGLT2i treatment, supporting the potential of these drugs in mitigating HF-related muscle pathology.

22 Apr 2025·Neurology

Pearls & Oy-sters: Severe Myotonic Crisis Resembling Malignant Hyperthermia

Article

Author: McSherry, Megan L. ; Wadhwani, Anil R. ; McGuire, Jennifer ; Brandsema, John Frederick ; Aggarwal, Ashna ; Loscalzao, Steven ; Matesanz, Susan ; Lockman, Justin L.

Patients with myotonic disorders are at risk for severe generalized muscle contraction, referred to as a "myotonic crisis." For those patients with nondystrophic myotonia (NDM), the most common trigger of a myotonic crisis is exposure to succinylcholine. In this case, a 10-year-old female patient with NDM secondary to an SCN4A pathogenic variant developed a severe myotonic crisis in the setting of an upper respiratory infection and asthma flare treated with a beta-adrenergic agonist (ß-agonist). She presented with generalized rigidity and features of hypermetabolism resembling an anesthetic-related malignant hyperthermia. Management necessitated multidisciplinary collaboration, a complex intubation strategy, and an extended course in the pediatric intensive care unit. We suspected that this crisis was precipitated in part by continuous ß-agonist use during her initial asthma management. Treatments targeting sequential steps of the myocyte activation cascade tempered the contractile apparatus leading to clinical improvement in rigidity.

09 Apr 2025·The Journal of Neuroscience

MuSK Regulates Neuromuscular Junction Nav1.4 Localization and Excitability

Article

Author: Christian, Jan L ; Xi, Chengjie ; Arnold, William D ; Wang, Xueyong ; Wharton, Kristi A ; Jaime, Diego ; Shahtout, Justin L ; Fallon, Justin R ; Madigan, Laura A ; Rich, Mark M ; Feder, Rita E ; Ewing, Madison D ; Fish, Lauren A ; Funai, Katsuhiko ; Rich, Kelly A ; Chen, Isabella

The neuromuscular junction (NMJ) is the linchpin of nerve-evoked muscle contraction. Broadly, the NMJ transduces nerve action potentials into muscle fiber action potentials (MFAPs). Efficient neuromuscular transmission requires cholinergic signaling, which generates endplate potentials (EPPs), and excitation, the amplification of an EPP by postsynaptic voltage-gated sodium channels (Nav1.4) to generate the MFAP. Compared to the cholinergic component, the signaling pathways that organize Nav1.4 are poorly characterized. Muscle-specific kinase (MuSK), in addition to its Ig1 domain-dependent role as the main organizer of acetylcholine receptors (AChRs), also binds BMPs via its Ig3 domain and shapes BMP-induced signaling. Using mice lacking the MuSK Ig3 domain (“ΔIg3-MuSK”), we probed the role of this domain at the NMJ. NMJs formed in ΔIg3-MuSK animals with pre- and postsynaptic specializations aligned at all ages examined. However, the ΔIg3-MuSK postsynaptic apparatus was fragmented from an early age. Synaptic electrophysiology showed that spontaneous and nerve-evoked acetylcholine release, AChR density, and endplate currents were comparable at WT and ΔIg3-MuSK NMJs. However, single fiber electromyography revealed that nerve-evoked MFAPs in ΔIg3-MuSK muscle were abnormal, exhibiting jitter and blocking. Nerve-evoked compound muscle action potentials and muscle force were also diminished. Finally, Nav1.4 levels were reduced at ΔIg3-MuSK NMJs, but not extrasynaptically, indicating that the observed excitability defects result from impaired synaptic localization of this ion channel. We propose distinct, domain-specific roles for MuSK at the NMJ: the Ig1 domain mediates agrin-LRP4-mediated AChR localization, while the Ig3 domain maintains postsynaptic Nav1.4 density, conferring the muscle excitability required to amplify cholinergic signals and trigger action potentials.

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SCN4A

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