Sulayman Dib-Hajj, PhD
Professor of NeurologyCards
Appointments
Additional Titles
Associate Director, Center for restoration of Nervous System Function, Veterans Affairs Medical center
Contact Info
Appointments
Additional Titles
Associate Director, Center for restoration of Nervous System Function, Veterans Affairs Medical center
Contact Info
Appointments
Additional Titles
Associate Director, Center for restoration of Nervous System Function, Veterans Affairs Medical center
Contact Info
About
Titles
Professor of Neurology
Associate Director, Center for restoration of Nervous System Function, Veterans Affairs Medical centerBiography
Professor in the Department of Neurology and the Center for Neuroscience and Regeneration Research, and the Center for Restoration of Nervous System Function, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut.
After earning a B.S. (1977) and M.S. (1982) degrees from the American University of Beirut, Lebanon, I earned my doctorate degree in 1990 from the Molecular, Cellular, and Developmental Biology (MCDB) program at the Ohio State University, Columbus, Ohio.
My research focuses on the role of voltage-gated sodium channels in inherited and acquired pain disorders. I have been investigating the effect of mutations on biophysical properties and trafficking of sodium channels, leading to regulation of neuronal excitability. I have also investigated modulation of sodium channels by post-translational modifications (phosphorylation) and by interaction with cytosolic protein partners. A more recent focus is using live imaging to study channel trafficking in sensory axons.
I serve on the editorial boards of the journals Frontiers in Pharmacology of Ion Channels and Channelopathies and Molecular Pain. I served as an Associate editor for The Journal of Neurosciences (2010-2015). I have served as a permanent member of Merit review panel for Medical Research Service (NURB/NURP) for the Veterans Administration (2012-2022). I have also served as an ad hoc reviewer on VA and NIH study sections and for national and international funding agencies, and for several scientific publications.I serve on the Board of Directors of the National Disease Research Interchange, a non-profit organization that supports the use of human tissue for research.
I am a member of the Society for Neurosciences, the International Association for the Study of Pain, the American Society for Biochemistry and Molecular Biology, and the American Association for the Advancement of Science.
Appointments
Neurology
ProfessorPrimary
Other Departments & Organizations
Education & Training
- PhD
- Ohio State University (1990)
- MS
- The American University of Beirut, Biology (1982)
- BS
- The American University of Beirut, Biology (1977)
Research
Overview
My research has focused on studying voltage-gated sodium channels regulation by accessory proteins and phosphorylation, and the contribution of specific channels to electrogenesis in dorsal root ganglion (DRG) neurons under normal conditions and in inherited channelopathies. Sodium channels are heterotrimers consisting of a large pore-forming alpha-subunit (referred to as channel), and smaller auxiliary beta-subunits. Sodium channels are large polypeptides (1700-2000 amino acids) which fold into four domains (DI-DIV), each domain including six transmembrane segments, linked by three loops (L1-L3). Nine alpha-subunits (Nav1.1-Nav1.9) encoded by the SCN1A-SCN5A and SCN8A-SCN11A genes, have been identified in mammals, and their expression is spatially-, and temporally-regulated. Different channels activate and inactivate with different kinetics and voltage-dependent properties, with six channels (Nav1.1-1.4, Nav1.6 and Nav1.7) sensitive to block by nanomolar concentrations of tetrodotoxin (TTX-S), and three channels (Nav1.5, Nav1.8 and Nav1.9) resistant to this blocker (TTX-R). Because channel properties are cell-type dependent and sodium channel properties can be modulated in a cell-type-specific manner, we have developed methods to study these channels within native neurons.
Neuronal sodium channels, Nav1.3, Nav1.6, Nav1.7, Nav1.8 and Nav1.9 have been intensively investigated because of their potential role in nervous system disorders. Specifically, Nav1.6-Nav1.9 are the main channels in DRG neurons, and their altered expression and modulation following injury or inflammation have been linked to acquired neuropathic pain in animal models. Electrophysiological studies over the past decade from our group and several other research groups have attributed specific roles for individual channels to specific aspects of action potential firing. Thus, in small-diameter nociceptive neurons Nav1.7 and Nav1.9 are considered threshold channels that boost weak stimuli and Nav1.8 is the channel that carries the main sodium current of action potentials with Nav1.6 contributing to the first few spikes. In large-diameter DRG neurons Nav1.6 is the main sodium channel with Nav1.7 and Nav1.8 present in a smaller number of these cells. Mutations in Nav1.7 have been shown to underlie two distinct pain disorders, while its complete loss results in congenital insensitivity to pain. Ongoing studies aim to better understand the contribution of these channels to the pathophysiology of pain and other neurological disorders, including multiple sclerosis and spinal cord injury.
Using genetic, biochemical, and electrophysiological approaches we have identified channel partners that may be important for channel trafficking and /or modulation. We have shown that members of the intracellular fibroblast growth factors (FGF11-14) can regulate biophysical properties of sodium channels Nav1.2, Nav1.3, Nav1.6 and Nav1.7. We have also identified and characterized CAP-1A, a cytosolic protein which binds selectively to Nav1.8, among sodium channels, and induce a reduction in the current density in DRG neurons. CAP-1A also binds to clathrin, and may represent a new class of adaptor proteins which link sodium channels and clathrin and regulate sodium channel density by clathrin-mediated endocytosis. We have also reported that contactin, a GPI-anchored cell adhesion moleculae, regulates the sodium channel density of Nav1.3, Nav1.8 and Nav1.9, but not Nav1.6 and Nav1.7. We are continuing this line of investigation to investigate isoform-specific regulation of sodium channels by these, and other newly-discovered channel partners.
Phosphorylation of ion channels is a rapid and reversible that may significantly alter neuronal physiology, and phosphorylation of sodium channels is predicted to acutely regulate DRG neuron firing under pathological conditions. It is well-established that tissue and nerve injury cause the release of pro-nociceptive cytokines and growth factors, and alter ion conductances, leading to sensitization and hyperexcitability of nociceptive neurons. For example, TNF-a, a major pro-nociceptive cytokine and other pro-nociceptive factors including neurotrophic growth factor (NGF) activate downstream signaling pathways including the mitogen-activated protein kinase (MAPK) p38 (stress activated MAPK) and ERK1/2 (extracellular regulated kinase), a process which has been implicated in inducing hyperexcitability of injured DRG neurons. In fact, published work has shown that acute application of TNF-a to DRG neurons in culture increases the TTX-R current density in a p38-dependent manner. These results suggest that Nav1.8 current density may be regulated by activated p38. We have designed experiments to answer the question of whether the Nav1 channels are substrates for direct phosphorylation by activated p38 MAPK, or whether phosphorylation of the channel is necessary for the increase in current density. Additional studies aim to investigate the effect of p38 and ERK1/2 on different sodium channel isoforms that are co-expressed within the same neuron.
MAP kinases are proline-directed serine/threonine kinases which phosphorylate SP or TP sites in their substrates. We have identified several potential MAPK phosphoacceptor sites within cytoplasmic regions of sodium channels, suggesting that they may be MAPK substrates during pain signal transduction. Using in vitro kinase assays on individual channel fragments, we have now shown that loop 1 (L1), which joins domains I and II, carries a single p38 phosphorylation site in Nav1.6 and two sites in Nav1.8. Interestingly these phosphoacceptor sites are part of a PXSP motif, the minimal PXXP motif that binds proteins with SH3 domains. Also PXpSP motif is a potential binding motif of the type 4 WW domain of some ubiquitin ligases. Thus phosphorylation of these sites within Nav1.6 and Nav1.8 may act as a switch that permits binding or un-binding of channel partners, leading to regulation of these sodium channels. Indeed, we have shown that activation of p38 increases Nav1.8 current density while it reduces Nav1.6 current density. Our findings suggest that p38 directly modulates Nav1.6 and Nav1.8 in vivo, providing a rapid mechanism that can regulate nociceptive neuron excitability following injury. Ongoing studies aim to elucidate mechanisms that underlie the p38-mediated, isoform-specific regulation of sodium channels, and toinvestigate the effect of p38 and ERK1/2 on other sodium channels within DRG neurons.
While the role of sodium channels in acquired channelopathies leading to neuropathic pain is well-established, their role in inherited painful neuropathies has been less clear. However, the recent discovery of a monogenic link of Nav1.7 to pain disorders in humans provided a compelling case for establishing Nav1.7 as central to pain-signaling. Dominant gain-of-function mutations in SCN9A, the gene that encodes sodium channel Nav1.7, have been linked to two severe pain syndromes, inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD), while recessive loss-of-function mutations have been linked to complete insensitivity to pain (CIP). Electrophysiological characterization of these mutations has elucidated molecular basis for altered excitability of DRG neurons that express these mutant channels, thus establishing a mechanistic link to human pain. Additional genetic studies have validated to role of Nav1.8 and Nav1.9 in human pain disorders including small fiber neuropathy.
More recently we developed tools and methods to study the trafficking of Nav channels in live sensory neurons. These studies are beginning to describe dynamic regulation of Nav and other ion channels in sensory axons under conditions that mimic disease states.
Together, these data provide a compelling rationale to target peripheral Nav channels (Nav1.7, Nav1.8 and Nav1.9) for the development of new pain therapeutic agents which are predicted to have minimal side effects.
- Identification and characterization of mutations in peripheral voltage-gated sodium channels in patients with heritable pain disorders.
- Investigate the contribution of individual sodium channel isoforms to firing properties of pain-sensing neurons
- Identification and characterization of sodium channel partners that modulate channel function, protein stability and trafficking.
- Testing small molecule inhibitors and gene therapy approaches to regulate excitability of DRG neurons as a prelude to testing them in clinical studies.
Medical Subject Headings (MeSH)
Research at a Glance
Yale Co-Authors
Publications Timeline
Research Interests
Stephen Waxman, MD, PhD
Mark Estacion, PhD
Peng Zhao, PhD
Mohammad-Reza Ghovanloo, PhD
Shujun Liu
Xiaoyang Cheng
Sodium Channels
Neurons
Voltage-Gated Sodium Channels
Nervous System Diseases
Publications
2024
Disordered but effective: short linear motifs as gene therapy targets for hyperexcitability disorders
Dib-Hajj S, Waxman S. Disordered but effective: short linear motifs as gene therapy targets for hyperexcitability disorders. Journal Of Clinical Investigation 2024, 134: e182198. PMID: 38949022, PMCID: PMC11213459, DOI: 10.1172/jci182198.Peer-Reviewed Original ResearchMeSH Keywords and ConceptsConceptsTetrodotoxin-sensitiveHyperexcitability disordersSensory neuronsExcitability of sensory neuronsGene therapy modalitiesPeripheral sensory neuronsVoltage-gated sodiumMinimal side effectsGene therapyInduce analgesiaTherapy modalitiesSide effectsTherapeutic strategiesNav channelsAttenuating excitationIn vivoHyperexcitabilityAnalgesiaNeuronsDisordersPainTherapyGenesBiodistributionRatsReal-time imaging of axonal membrane protein life cycles
Tyagi S, Higerd-Rusli G, Akin E, Baker C, Liu S, Dib-Hajj F, Waxman S, Dib-Hajj S. Real-time imaging of axonal membrane protein life cycles. Nature Protocols 2024, 1-32. PMID: 38831222, DOI: 10.1038/s41596-024-00997-x.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsAltmetricConceptsMembrane proteinsRecycling of membrane proteinsProtein subcellular localizationMembrane protein homeostasisMembrane protein traffickingEngineered membrane proteinsMultiple membrane proteinsSelf-labeling tagsCell culturesProtein traffickingProtein tagsSubcellular localizationProtein homeostasisSpatiotemporal regulationCellular processesMultiple proteinsSubcellular distributionVesicular packagingThroughput mannerProteinNeuronal compartmentsDistal axonsProtein spatial organizationFluorescent labelingNeuronal culturesNav1.8 in small dorsal root ganglion neurons contributes to vincristine-induced mechanical allodynia
Nascimento de Lima A, Zhang H, Chen L, Effraim P, Gomis-Perez C, Cheng X, Huang J, Waxman S, Dib-Hajj S. Nav1.8 in small dorsal root ganglion neurons contributes to vincristine-induced mechanical allodynia. Brain 2024, awae071. PMID: 38447953, DOI: 10.1093/brain/awae071.Peer-Reviewed Original ResearchConceptsDorsal root ganglion neuronsDorsal root ganglionVincristine-induced mechanical allodyniaVincristine-induced peripheral neuropathyMechanical allodyniaVincristine treatmentNav1.8 channelsSmall dorsal root ganglion neuronsDevelopment of mechanical allodyniaTTX-R current densityVoltage-gated sodium channel Nav1.6Vincristine-treated animalsCurrent-clamp recordingsSodium channel Nav1.8Voltage-clamp recordingsReducing current thresholdSodium channel Nav1.6Investigate pathophysiological mechanismsTTX-RHyperpolarizing shiftRoot ganglionAllodyniaGanglion neuronsVincristine administrationPeripheral neuropathyTRPM8 mutations associated with persistent ocular pain after refractive surgery: D665N and V915M
Ghovanloo M, Effraim P, Tyagi S, Cheng X, Yuan J, Schulman B, Jacobs D, Dib-Hajj S, Waxman S. TRPM8 mutations associated with persistent ocular pain after refractive surgery: D665N and V915M. Biophysical Journal 2024, 123: 391a. DOI: 10.1016/j.bpj.2023.11.2376.Peer-Reviewed Original ResearchA corneal neuralgia TRPV1 mutation increases response to acidic pH and alters agonist sensitization and desensitization
Gualdani R, Gailly P, Barbeau S, Jacobs D, Dib-Hajj S, Waxman S. A corneal neuralgia TRPV1 mutation increases response to acidic pH and alters agonist sensitization and desensitization. Biophysical Journal 2024, 123: 391a. DOI: 10.1016/j.bpj.2023.11.2378.Peer-Reviewed Original ResearchFunctionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol
Ghovanloo M, Effraim P, Tyagi S, Zhao P, Dib-Hajj S, Waxman S. Functionally-selective inhibition of threshold sodium currents and excitability in dorsal root ganglion neurons by cannabinol. Communications Biology 2024, 7: 120. PMID: 38263462, PMCID: PMC10805714, DOI: 10.1038/s42003-024-05781-x.Peer-Reviewed Original ResearchAltmetricMeSH Keywords and ConceptsConceptsDorsal root ganglionDorsal root ganglion neuronal excitabilityDorsal root ganglion neuronsNeuronal excitabilityCurrent-clamp analysisSteady-state inactivationVoltage-dependent sodiumSlow inactivated stateAutomated patch clamp platformMultielectrode array recordingsNav currentsNeuropathic painSodium currentRoot ganglionGanglion neuronsSlow inactivationInactivated stateCurrent inhibitorsIon channelsNeuronsInhibitory effectCannabinolArray recordingsEndocannabinoidCannabinoidCompartment-specific regulation of NaV1.7 in sensory neurons after acute exposure to TNF-α
Tyagi S, Higerd-Rusli G, Ghovanloo M, Dib-Hajj F, Zhao P, Liu S, Kim D, Shim J, Park K, Waxman S, Choi J, Dib-Hajj S. Compartment-specific regulation of NaV1.7 in sensory neurons after acute exposure to TNF-α. Cell Reports 2024, 43: 113685. PMID: 38261513, PMCID: PMC10947185, DOI: 10.1016/j.celrep.2024.113685.Peer-Reviewed Original ResearchCitationsAltmetricConceptsTNF-aSensory neuronsEffect of TNF-aSensory neuron excitabilityTumor necrosis factor-aRegulation of NaV1.7Voltage-gated sodiumPro-inflammatory cytokinesCompartment-specific effectsNeuronal plasma membraneSensitize nociceptorsNeuronal excitabilitySomatic membraneChannel N terminusElectrophysiological recordingsP38 MAPKIon channelsFactor AAcute exposureMolecular determinantsNeuronsAxonal endingsPhospho-acceptor sitesPlasma membraneCompartment-specific regulation
2023
Sodium currents in naïve mouse dorsal root ganglion neurons: No major differences between sexes
Ghovanloo M, Tyagi S, Zhao P, Effraim P, Dib-Hajj S, Waxman S. Sodium currents in naïve mouse dorsal root ganglion neurons: No major differences between sexes. Channels 2023, 18: 2289256. PMID: 38055732, PMCID: PMC10761158, DOI: 10.1080/19336950.2023.2289256.Peer-Reviewed Original ResearchCitationsAltmetricMeSH Keywords and ConceptsConceptsSexual dimorphismRodent dorsal root ganglion neuronsBiophysical propertiesDorsal root ganglion neuronsExpression patternsSex-dependent regulationVoltage-gated sodiumFunctional analysisGanglion neuronsRodent sensory neuronsMouse dorsal root ganglion neuronsNaïve WT miceNumber of cellsMixed populationDimorphismUniform experimental conditionsSex-dependent differencesSensory neuronsNative DRG neuronsPain pathwaysDRG neuronsWT miceClinical studiesNav currentsAdult malesLessons learned in translating pain knowledge into practice
Becker J, Effraim P, Dib-Hajj S, Rittner H. Lessons learned in translating pain knowledge into practice. PAIN Reports 2023, 8: e1100. PMID: 37928204, PMCID: PMC10624476, DOI: 10.1097/pr9.0000000000001100.Peer-Reviewed Original ResearchCitationsAltmetricConceptsPain knowledgeCalcitonin gene-related peptide antagonistsGrowth factorNovel pain treatmentsClinical phase IISevere side effectsMechanisms of nociceptionBetter preclinical modelsNeuronal growth factorsHands of cliniciansLack of effectMore patientsMusculoskeletal painPain treatmentChronic painClinical updateNew analgesicsClinical trialsNeurokinin receptorsPreclinical modelsPreclinical studiesSide effectsPatientsJoint replacementAvailable evidenceNaV1.7: A central role in pain
Waxman S, Dib-Hajj S. NaV1.7: A central role in pain. Neuron 2023, 111: 2615-2617. PMID: 37678164, DOI: 10.1016/j.neuron.2023.08.011.Peer-Reviewed Original ResearchCitationsAltmetric
Academic Achievements and Community Involvement
activity Reviewer
Peer Review Groups and Grant Study SectionsVA/NURBDetails06/01/2012 - Presentactivity Board Member
Peer Review Groups and Grant Study SectionsFrontiers in Pharmacology of Ion Channels and Channelopathies• Review Editorial BoardDetails12/01/2012 - Presentactivity Board Member
Peer Review Groups and Grant Study SectionsMolecular PainDetails12/01/2015 - Presentactivity Member
Peer Review Groups and Grant Study SectionsThe journal of NeuroscienceDetails2010 - 2015activity Editor
Peer Review Groups and Grant Study SectionsNeuroscience LettersDetails10/07/2009 - 12/31/2010
Links & Media
News
- February 16, 2022
NIH Awards HEAL Grant to Study Novel Ways to Treat Pain
- October 23, 2019
Scientists Discover How Nerve Cells Build Their Electrically Excitable Membranes
- December 04, 2018
Scientists Identify Method to Study Resilience to Pain
- April 18, 2016
Personalized treatment for chronic pain closer to reality