About

Stephen C. Cannon, MD, PhD, is a Professor in the Department of Physiology in the David Geffen School of Medicine at UCLA. His educational background includes a B.S. and M.S. in Mechanical Engineering from Washington University in St. Louis, where his master's thesis explored how increased muscle stiffness and the intensity of the stretch reflex with mechanical loading produce an instability that may cause tremor. He then entered the Medical Scientists Training Program at Johns Hopkins, working with Prof. David Robinson to identify the locus of the brainstem neural integrator for the oculomotor system and demonstrating the importance of lateral inhibition in this premotor circuit. After completing a medical internship and neurology residency at Massachusetts Hospital, where he served as chief resident in 1990, Dr. Cannon completed a research postdoctoral fellowship in David Corey's lab, making a fundamental discovery of the sodium channel defect causing susceptibility to periodic paralysis. His research focuses on ion channelopathies of skeletal muscle, specifically how ion channels regulate electrical excitability and how mutations lead to human disease. His laboratory investigates inherited disorders of skeletal muscle caused by mutations in voltage-gated ion channels, which can result in conditions such as myotonia and periodic paralysis. The lab studies the effects of mutations on channel function, employs computational models of muscle excitability, and develops genetically-engineered mouse models to understand disease mechanisms and test potential therapeutics. Notably, his work has identified gain-of-function defects in the NaV1.4 sodium channel that predispose individuals to myotonia and periodic paralysis, providing mechanistic insights into these disorders. His recent research explores how mutations in the voltage-sensor domain of NaV1.4 or CaV1.1 contribute to susceptibility to hypokalemic periodic paralysis through gating pore 'leak' mechanisms. His models have demonstrated that these mutations are sufficient to cause myotonia or paralysis and have shown that inhibitors of the Na-K-2Cl transporter can reverse or prevent attacks of weakness, advancing potential therapeutic strategies.

Research topics

• Biochemistry
• Biology
• Chemistry
• Biophysics
• Medicine
• Neuroscience
• Internal medicine
• Anesthesia
• Surgery

Selected publications

• Efficacy of a K ⁺ Channel Agonist, <scp>XEN1101</scp> , For Preserving Contractility in Mouse Models of Hypokalemic Periodic Paralysis

  Muscle & Nerve · 2026-01-21

  articleOpen accessSenior authorCorresponding

  ABSTRACT Introduction/Aims Effective management remains lacking for recurrent episodes of acute weakness in hypokalemic periodic paralysis (HypoPP). We assessed the efficacy of a second‐generation potassium channel agonist, XEN1101, to prevent and abort the low‐K + induced loss of force in mouse models of HypoPP. Methods An ex vivo contractility assay was used to interrogate the efficacy of XEN1101 for preserving contractile force and for enhancing recovery of force in the setting of a low‐K + challenge for HypoPP mice carrying the sodium channel Na V 1.4‐R669H or the calcium channel Ca V 1.1‐R528H mutations. Results The acute loss of force for HypoPP muscle, triggered by a 2 mM K + challenge, was prevented by low micromolar XEN1101, with an effective concentration of 0.30 μM for 50% protection. Application of 1 μM XEN1101, after the onset of 2 mM K + induced weakness, restored the peak contractile force (70%–100% of baseline). Discussion The K V 7 potassium channel agonist XEN1101 is effective as both a prophylactic agent and as abortive therapy for management of low‐K + induced weakness in murine models of HypoPP. XEN1101 is more potent than the first‐generation Kv7 agonist, retigabine, in our murine models of HypoPP and is also better tolerated in patients. These improvements provide a rationale for future clinical trials of XEN1101 in HypoPP patients.

  PublisherOA PDFDOI

• Potassium-sensitive loss of muscle force in the setting of reduced inward rectifier K ⁺ current: Implications for Andersen–Tawil syndrome

  Proceedings of the National Academy of Sciences · 2025-03-26 · 4 citations

  articleOpen accessSenior authorCorresponding

  Andersen–Tawil syndrome (ATS) is an ion channelopathy with variable penetrance for the triad of periodic paralysis, arrhythmia, and dysmorphia. Dominant-negative mutations of KCNJ2 encoding the Kir2.1 potassium channel subunit are found in 60% of ATS families. As with most channelopathies, episodic attacks in ATS are frequently triggered by environmental stresses: exercise for periodic paralysis or stress with adrenergic stimulation for arrhythmia. Fluctuations in K + , either low or high, are potent triggers for attacks of weakness in other variants of periodic paralysis (hypokalemic periodic paralysis or hyperkalemic periodic paralysis). For ATS, the [K + ] dependence is less clear; with reports describing weakness in high-K + or low-K + . Patient trials with controlled K + challenges are not possible, due to arrhythmias. We have developed two mouse models (genetic and pharmacologic) with reduced Kir currents, to address the question of K + -sensitive loss of force. These animal models and computational simulations both show K + -dependent weakness occurs only when Kir current is &lt;30% of wildtype. As the Kir deficit becomes more severe, the phenotype shifts from high-K + -induced weakness to a combination where either high-K + or low-K + triggers weakness. A K + channel agonist, retigabine, protects muscle from K + -sensitive weakness in our mouse models of the skeletal muscle involvement in ATS.

  PublisherOA PDFDOI

• The molecular transition that confers voltage dependence to muscle contraction

  Nature Communications · 2025-05-24 · 5 citations

  articleOpen access

  Abstract What is the molecular origin of voltage dependence in skeletal muscle excitation-contraction? Cholinergic transmission to the muscle fiber triggers action potentials, which are sensed by voltage-gated L-type calcium channels (Ca V 1.1). In turn, the conformational changes in Ca V 1.1 propagate to and activate intracellular ryanodine receptors (RyR1), causing Ca 2+ release and contraction. The Ca V 1.1 channel has four voltage-sensing domains (VSD-I to -IV) with diverse voltage-sensing properties, so the identity of VSD(s) responsible for conferring voltage dependence to RyR1 opening, is unknown. Using voltage-clamp fluorometry, we show that only VSD-III possesses kinetic, voltage-dependent and pharmacological properties consistent with skeletal-muscle excitability and Ca 2+ release. We propose that the earliest voltage-dependent event in the excitation-contraction process is the structural rearrangement of VSD-III that propagates to RyR1 to initiate Ca 2+ release and contraction.

  PublisherOA PDFDOI

• Periodic paralysis

  Handbook of clinical neurology · 2024-01-01 · 5 citations

  reviewOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Retigabine suppresses loss of force in mouse models of hypokalaemic periodic paralysis

  Brain · 2023-01-30 · 9 citations

  articleOpen accessSenior authorCorresponding

  Recurrent episodes of weakness in periodic paralysis are caused by intermittent loss of muscle fibre excitability, as a consequence of sustained depolarization of the resting potential. Repolarization is favoured by increasing the fibre permeability to potassium. Based on this principle, we tested the efficacy of retigabine, a potassium channel opener, to suppress the loss of force induced by a low-K+ challenge in hypokalaemic periodic paralysis (HypoPP). Retigabine can prevent the episodic loss of force in HypoPP. Knock-in mutant mouse models of HypoPP (Cacna1s p.R528H and Scn4a p.R669H) were used to determine whether pre-treatment with retigabine prevented the loss of force, or post-treatment hastened recovery of force for a low-K+ challenge in an ex vivo contraction assay. Retigabine completely prevents the loss of force induced by a 2 mM K+ challenge (protection) in our mouse models of HypoPP, with 50% inhibitory concentrations of 0.8 ± 0.13 μM and 2.2 ± 0.42 μM for NaV1.4-R669H and CaV1.1-R528H, respectively. In comparison, the effective concentration for the KATP channel opener pinacidil was 10-fold higher. Application of retigabine also reversed the loss of force (rescue) for HypoPP muscle maintained in 2 mM K+. Our findings show that retigabine, a selective agonist of the KV7 family of potassium channels, is effective for the prevention of low-K+ induced attacks of weakness and to enhance recovery from an ongoing loss of force in mouse models of type 1 (Cacna1s) and type 2 (Scn4a) HypoPP. Substantial protection from the loss of force occurred in the low micromolar range, well within the therapeutic window for retigabine.

  PublisherOA PDFDOI

• Voltage-Dependent Ca ²⁺ Release Is Impaired in Hypokalemic Periodic Paralysis Caused by Ca _V 1.1-R528H but not by Na _V 1.4-R669H

  bioRxiv (Cold Spring Harbor Laboratory) · 2022-05-19

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Hypokalemic periodic paralysis (HypoPP) is a channelopathy of skeletal muscle caused by missense mutations in the voltage sensor domains (usually at an arginine of the S4 segment) of the Ca V 1.1 calcium channel or of the Na V 1.4 sodium channel. The primary clinical manifestation is recurrent attacks of weakness, resulting from impaired excitability of anomalously depolarized fibers containing leaky mutant channels. While the ictal loss of fiber excitability is sufficient to explain the acute episodes of weakness, a deleterious change in voltage sensor function for Ca V 1.1 mutant channels may also compromise excitation-contraction coupling (EC-coupling). We used the low-affinity Ca 2+ indicator OGN-5 to assess voltage-dependent Ca 2+ -release as a measure of EC-coupling for our knock-in mutant mouse models of HypoPP. The peak Δ F/F 0 in fibers isolated from Ca V 1.1-R528H mice was about two-thirds of the amplitude observed in WT mice; whereas in HypoPP fibers from Na V 1.4-R669H mice the Δ F/F 0 was indistinguishable from WT. No difference in the voltage dependence of Δ F/F 0 from WT was observed for fibers from either HypoPP mouse model. Because late-onset permanent muscle weakness is more severe for Ca V 1.1-associated HypoPP than for Na V 1.4, we propose the reduced Ca 2+ -release for Ca V 1.1-R528H mutant channels may increase the susceptibility to fixed myopathic weakness. In contrast the episodes of transient weakness are similar for Ca V 1.1- and Na V 1.4-associated HypoPP, consistent with the notion that acute attacks of weakness are primarily caused by leaky channels and are not a consequence of reduced Ca 2+ -release.

  PublisherOA PDFDOI

• Voltage-dependent Ca ²⁺ release is impaired in hypokalemic periodic paralysis caused by Ca _V 1.1-R528H but not by Na _V 1.4-R669H

  American Journal of Physiology-Cell Physiology · 2022-06-27 · 4 citations

  articleOpen accessSenior authorCorresponding

  Hypokalemic periodic paralysis (HypoPP) is a channelopathy of skeletal muscle caused by missense mutations in the voltage sensor domains (usually at an arginine of the S4 segment) of the Ca V 1.1 calcium channel or of the Na V 1.4 sodium channel. The primary clinical manifestation is recurrent attacks of weakness, resulting from impaired excitability of anomalously depolarized fibers containing leaky mutant channels. Although the ictal loss of fiber excitability is sufficient to explain the acute episodes of weakness, a deleterious change in voltage sensor function for Ca V 1.1 mutant channels may also compromise excitation-contraction coupling (EC-coupling). We used the low-affinity Ca 2+ indicator Oregon Green 488 BAPTA-5N (OGB-5N) to assess voltage-dependent Ca 2+ -release as a measure of EC-coupling for our knock-in mutant mouse models of HypoPP. The peak Δ F/ F 0 in fibers isolated from Ca V 1.1-R528H mice was about two-thirds of the amplitude observed in WT mice; whereas in HypoPP fibers from Na V 1.4-R669H mice the Δ F/ F 0 was indistinguishable from WT. No difference in the voltage dependence of Δ F/ F 0 from WT was observed for fibers from either HypoPP mouse model. Because late-onset permanent muscle weakness is more severe for Ca V 1.1-associated HypoPP than for Na V 1.4, we propose that the reduced Ca 2+ -release for Ca V 1.1-R528H mutant channels may increase the susceptibility to fixed myopathic weakness. In contrast, the episodes of transient weakness are similar for Ca V 1.1- and Na V 1.4-associated HypoPP, consistent with the notion that acute attacks of weakness are primarily caused by leaky channels and are not a consequence of reduced Ca 2+ -release.

  PublisherOA PDFDOI

• A multicenter, prospective, cross-sectional, genotype-phenotype and longitudinal natural history study of Andersen-Tawil syndrome

  medRxiv · 2022-05-30

  preprintOpen access

  ABSTRACT Objective A multi-center, prospective, cross-sectional natural history study to define the clinical phenotype of Andersen-Tawil syndrome, validate its current diagnostic criteria, explore genotype-phenotype correlations, and establish clinically relevant endpoints for use in therapeutic trials. Methods Participants were followed at yearly intervals for two years. Outcome measures included attack frequency and duration, neurophysiological exercise testing and interictal muscle strength. Cardiac endpoints were QTc interval, presence of U-waves, frequency of ventricular ectopy and arrhythmias. Participants completed the SF-36 and underwent KCNJ2 gene analysis. Results 28 participants were enrolled. The age range was 17 to 82 years. 23 participants harbored mutations in KCNJ2 , including a new mutation, Y68D. All exhibited at least one skeletal feature with 26/28 exhibiting two or more. Common physical abnormalities were a small mandible (89%), low set ears (82%) and micromelia of hands or feet (71%). 26 participants reported periodic paralysis. The frequency of attacks varied from 12/week to 1/year, and duration from 12 minutes to 21 days. Common triggers for attacks were prolonged rest (85%) and exercise/exertion (73%). 20/25 had an abnormal long exercise test. A prolonged QTc interval was identified in 36% participants, U waves in 39% and ambulatory ECGs demonstrated runs of ventricular tachycardia in 32% and more than 10 000 ventricular couples in 14% of participants. Interpretation There is extensive heterogeneity in both the spectrum and severity of Andersen-Tawil syndrome. Overall, the symptoms result in a significant impairment in quality of life. The cardiac and neurophysiological data could serve as outcome measures in future treatment trials.

  PublisherOA PDFDOI

• Retigabine Suppresses Loss of Force in a Mouse Model of Hypokalemic Periodic Paralysis

  bioRxiv (Cold Spring Harbor Laboratory) · 2022-05-21

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Objective The goal of this experimental study was to test the hypothesis that the potassium channel opener retigabine can prevent the episodic loss of force in hypokalemic periodic paralysis (HypoPP). Methods A knock-in mutant mouse model of HypoPP ( Scn4a p.R669H) was used to determine whether pretreatment with retigabine suppressed the loss of force, or post-treatment hastened recovery of force for a low-K + challenge in an ex vivo contraction assay. Results Retigabine completely prevents the loss of force induced by a 2 mM K + challenge (protection) in our mouse model of HypoPP, with a 50% inhibitory concentration (IC 50 ) of 0.8 µM. In comparison, the effective concentration for the K ATP channel opener pinacidil was ten-fold higher. Application of retigabine also reversed the loss of force (rescue) for HypoPP muscle maintained in 2 mM K + . Interpretation Retigabine, a selective agonist of the K V 7 family of potassium channels, is effective for the prevention of low-K + induced attacks of weakness and to enhance recovery from an on-going loss of force in a mouse model of HypoPP. Substantial protection from the loss of force occurred in the low micromolar range, well within the therapeutic window for retigabine.

  PublisherOA PDFDOI

• Decision letter: The mechanism underlying transient weakness in myotonia congenita

  2021-02-03

  peer-reviewOpen accessSenior author

  Myotonia is a neuromuscular condition that causes problems with the relaxation of muscles following voluntary movements. One type of myotonia is Becker disease, also called recessive myotonia congenita. This is a genetic condition that causes muscle stiffness as a result of involuntary muscle activity. Patients may also suffer transient weakness for a few seconds or as long as several minutes after initiating a movement. The cause of these bouts of temporary weakness is still unclear, but there are hints that it could be linked to the muscle losing its excitability, the ability to respond to the stimuli that make it contract. However, this is at odds with findings that show that muscles in Becker disease are hyperexcitable. Muscle excitability depends on the presence of different concentrations of charged ions (positively charged sodium, calcium and potassium ions and negatively charged chloride ions) inside and outside of each muscle cells. These different concentrations of ions create an electric potential across the cell membrane, also called the ‘membrane potential’. When a muscle cell gets stimulated, proteins on the cell membrane known as ion channels open. This allows the flow of ions between the inside and the outside of the cell, which causes an electrical current that triggers muscle contraction. To better understand the causes behind this muscle weakness, Myers et al. used mice that had either been genetically manipulated or given drugs to mimic Becker disease. By measuring both muscle force and the electrical currents that drive contraction, Myers et al. found that the mechanism underlying post-movement weakness involved a transient change in the concentrations of positively charged ions inside and outside the cells. Further experiments showed that proteins that regulate the passage of both sodium and calcium in and out of the cell – called sodium and calcium channels – contributed to this change in concentration. In addition, Myers et al. discovered that using a drug called ranolazine to stop sodium ions from entering the cell eliminated transient weakness in live mice. These findings suggest that in Becker disease, muscles cycle rapidly between being hyperexcited or not able to be excited, and that targeting the flow of sodium ions into the cell could be an effective treatment to prevent transient weakness in myotonia congenita. This study paves the way towards the development of new therapies to treat Becker disease as well as other muscle ion channel diseases with transient weakness such as periodic paralysis.

  PublisherDOI

Recent grants

• NIH Grant R01AR042703

  NIH · $3.7M · 2008

• Molecular Physiology of Myotonia and Periodic Paralysis

  NIH · $4.2M · 1994–2020

• Disease Pathogenesis and Modification for CaV1.1-Associated Hypokalemic Periodic Paralysis

  NIH · $5.9M · 2012–2028

Frequent coauthors

• Michael G. Hanna

  234 shared

• Perry B. Shieh

  225 shared

• Valeria Sansone

  University of Milan

  206 shared

• Jaya Trivedi

  Southwestern Medical Center

  206 shared

• Robert C. Griggs

  205 shared

• Rabi Tawil

  202 shared

• Richard J. Barohn

  201 shared

• G. Meola

  University of Milan

  201 shared

Education

• PhD, Biomedical Engineering

  Johns Hopkins School of Medicine

  1986

• MD

  Johns Hopkins School of Medicine

  1986

• BS / MS, Mechanical Engineering

  Washington University in Saint Louis

  1980