William A. Catterall

Ion channel regulation and function

University of Washington

About

Research focus

Ion channel regulation and function

Impact

690 pubs · 91,953 cites · h-index 162

Affiliations

Publications

Nutritional PsychiatryNano et al.Meta-Analysis

Vitamin D deficiency and depressive episodes in adolescents and young adults: systematic review and meta-analysis

Background We conducted a systematic review and meta-analysis to examine the association between vitamin D deficiency and depression in adolescents (10–17 years) and young adults (18–39 years). Methods We searched databases and reference lists (inception to October 2025, limited to English studies). We extracted data and assessed study quality using the Newcastle-Ottawa Scale. We used random-effects meta-analyses to determine mean difference scores in vitamin D serum levels (depressed vs. non-depressed), odds ratios for vitamin D categories (insufficiency and deficiency), and subgroup analyses (gender). We assessed statistical heterogeneity using I 2 , with leave-one-out as a sensitivity analysis. Results From 11,309 citations, we found 19 studies between 2010 and 2025 (mean=28,824; range: 51 to 483,683). Eleven studies (58%) found that vitamin D insufficiency (50–75 nmol/L) and deficiency (<50 nmol/L) were significantly associated with depression. Our meta-analysis revealed that the depressed population of young adults and adolescents had a significantly lower mean vitamin D levels than non-depressed participants (random-effect MD=-17.77 nmol/L [-30.12,-5.42]; p=0.005; I 2 =95%, heterogeneity P<0.001). We found a borderline significant association between depression and vitamin D deficiency (random-effect OR=2.06 [1.02, 4.17], p=0.05; I 2 =95%, heterogeneity P<0.001) but no association with vitamin D insufficiency (random-effect OR=0.94 [0.74, 1.21]; p>0.05; I 2 =0%, heterogeneity P>0.05). Leave-one-out sensitivity analysis produced overall consistent results. Female participants had a significantly stronger association (random-effect OR=1.96 [1.05, 3.63], p=0.03, I 2 =97%, heterogeneity P<0.001). Conclusion Our systematic review suggested that vitamin D deficiency is significantly associated with depression, with exploratory findings indicating potential variations by sex.

IUPHAR/BPS Guide to Pharmacology CITECatterall et al.Original Research

Voltage-gated calcium channels (CaV) in GtoPdb v.2025.3

This analysis reveals the organization of calcium channels, highlighting the structure of α1 subunits and their families.

Journal of Affective Disorders ReportsNano et al.Cross-Sectional Study

“I wish I could work on school stuff.” Investigating the impact of remote learning on undergraduate students’ academic success and mental health during the COVID-19 lockdown

• Majority of undergraduate students reported that remote learning negatively impacted their school performance. • Students with non-STEM college majors experienced higher levels of stress, anxiety, and depression compared to students with STEM college majors. • We found six common themes related to negative experiences with remote learning. To investigate how remote learning has affected undergraduate students' learning abilities, academic success, and mental health during the COVID-19 pandemic. This cross-sectional study took place between April and June 2020 in the United States. Participants completed a survey consisting of demographic questions, Depression, Anxiety, and Stress Scale-21 Items (DASS-21), and an open-ended question. We used a logistic regression model on objective variables and conducted a systematic thematic analysis of the open-ended response. Our final sample consisted of 1,173 full-time undergraduate students in the United States. Most participants were public university students ( n =835, 71.2 %) and reported that moving to remote learning had a negative impact on their school performance ( n =802, 68.4 %). Students’ positive experiences in remote learning were associated with moving to their family’s house ( p <0.05), living on campus in a dorm ( p <0.05), and no internet issues during classes ( p <0.0001). From the thematic analysis, we found six common themes among those who reported having a negative experience with remote learning that focused on the following topics: (1) Students had to adjust to an online learning environment; (2) Students had to adjust to the home environment; (3) Students experienced mental health difficulties; (4) Students dealt with political tension; (5) Students felt uncertain about future opportunities; and (6) Students lacked motivation to do work. The results of this study may not be generalizable to undergraduate students outside of the United States due to differences in lockdown restrictions. Remote learning during COVID-19 had a negative impact on the majority of undergraduate students’ academic performance and mental health.

Liu et al.Original Research

Bottom-up design of calcium channels from defined selectivity filter geometry

Native ion channels play key roles in biological systems, and engineered versions are widely used as chemogenetic tools and in sensing devices 1,2 . Protein design has been harnessed to generate pore-containing transmembrane proteins, but the capability to design ion selectivity based on the interactions between ions and selectivity filter residues, a crucial feature of native ion channels 3 , has been constrained by the lack of methods to place the metal-coordinating residues with atomic-level precision. Here we describe a bottom-up RFdiffusion-based approach to construct Ca 2+ channels from defined selectivity filter residue geometries, and use this approach to design symmetric oligomeric channels with Ca 2+ selectivity filters having different coordination numbers and different geometries at the entrance of a wide pore buttressed by multiple transmembrane helices. The designed channel proteins assemble into homogenous pore-containing particles, and for both tetrameric and hexameric ion-coordinating configurations, patch-clamp experiments show that the designed channels have higher conductances for Ca 2+ than for Na + and other divalent ions (Sr 2+ and Mg 2+ ). Cryo-electron microscopy indicates that the design method has high accuracy: the structure of the hexameric Ca 2+ channel is nearly identical to the design model. Our bottom-up design approach now enables the testing of hypotheses relating filter geometry to ion selectivity by direct construction, and provides a roadmap for creating selective ion channels for a wide range of applications.

Journal of Biological ChemistryWang et al.preclinical

Cardiac-selective Rad-/- mice exhibited higher baseline LVEF and basal cardiomyocyte L-type Ca2+ current than Rad+/+ controls, while AKAP-IS peptide completely abolished isoproterenol-induced L-type Ca2+ current upregulation in isolated cardiomyocytes.

This preclinical study demonstrates that AKAP-anchored PKA locally coordinates both the dissociation of the inhibitory GTPase Rad and the direct phosphorylation of the Cav1.2 cytoplasmic tail to achieve maximal β-adrenergic stimulation of cardiac L-type calcium currents and contractility.

Proceedings of the National Academy of SciencesEltokhi et al.Original Research

Pathogenic gating pore current conducted by autism-related mutations in the Na V 1.2 brain sodium channel

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social and communication deficits and repetitive behaviors. The genetic heterogeneity of ASD presents a challenge to the development of an effective treatment targeting the underlying molecular defects. ASD gating charge mutations in the KCNQ /K V 7 potassium channel cause gating pore currents (I gp ) and impair action potential (AP) firing of dopaminergic neurons in brain slices. Here, we investigated ASD gating charge mutations of the voltage-gated SCN2A /Na V 1.2 brain sodium channel, which ranked high among the ion channel genes with mutations in individuals with ASD. Our results show that ASD mutations in the gating charges R2 in Domain-II (R853Q), and R1 (R1626Q) and R2 (R1629H) in Domain-IV of Na V 1.2 caused I gp in the resting state of ~0.1% of the amplitude of central pore current. The R1626Q mutant also caused significant changes in the voltage dependence of fast inactivation, and the R1629H mutant conducted proton-selective I gp . These potentially pathogenic I gp were exacerbated by the absence of the extracellular Mg 2+ and Ca 2+ . In silico simulation of the effects of these mutations in a conductance-based single-compartment cortical neuron model suggests that the inward I gp reduces the time to peak for the first AP in a train, increases AP rates during a train of stimuli, and reduces the interstimulus interval between consecutive APs, consistent with increased neural excitability and altered input/output relationships. Understanding this common pathophysiological mechanism among different voltage-gated ion channels at the circuit level will give insights into the underlying mechanisms of ASD.

Nature CommunicationsTonggu et al.Original Research

Dual receptor-sites reveal the structural basis for hyperactivation of sodium channels by poison-dart toxin batrachotoxin

The poison dart toxin batrachotoxin is exceptional for its high potency and toxicity, and for its multifaceted modification of the function of voltage-gated sodium channels. By using cryogenic electron microscopy, we identify two homologous, but nonidentical receptor sites that simultaneously bind two molecules of toxin, one at the interface between Domains I and IV, and the other at the interface between Domains III and IV of the cardiac sodium channel. Together, these two bound toxin molecules stabilize α/π helical conformation in the S6 segments that gate the pore, and one of the bound BTX-B molecules interacts with the crucial Lys1421 residue that is essential for sodium conductance and selectivity via an apparent water-bridged hydrogen bond. Overall, our structure provides insight into batrachotoxin's potency, efficacy, and multifaceted functional effects on voltage-gated sodium channels via a dual receptor site mechanism.

ChannelsCatterallReview

Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology

Voltage-gated sodium channels initiate action potentials in nerve and muscle, and voltage-gated calcium channels couple depolarization of the plasma membrane to intracellular events such as secretion, contraction, synaptic transmission, and gene expression. In this Review and Perspective article, I summarize early work that led to identification, purification, functional reconstitution, and determination of the amino acid sequence of the protein subunits of sodium and calcium channels and showed that their pore-forming subunits are closely related. Decades of study by antibody mapping, site-directed mutagenesis, and electrophysiological recording led to detailed two-dimensional structure-function maps of the amino acid residues involved in voltage-dependent activation and inactivation, ion permeation and selectivity, and pharmacological modulation. Most recently, high-resolution three-dimensional structure determination by X-ray crystallography and cryogenic electron microscopy has revealed the structural basis for sodium and calcium channel function and pharmacological modulation at the atomic level. These studies now define the chemical basis for electrical signaling and provide templates for future development of new therapeutic agents for a range of neurological and cardiovascular diseases.

The Journal of General PhysiologyWisedchaisri et al.Original Research

Structural basis for severe pain caused by mutations in the voltage sensors of sodium channel NaV1.7

Voltage-gated sodium channels in peripheral nerves conduct nociceptive signals from nerve endings to the spinal cord. Mutations in voltage-gated sodium channel NaV1.7 are responsible for a number of severe inherited pain syndromes, including inherited erythromelalgia (IEM). Here, we describe the negative shifts in the voltage dependence of activation in the bacterial sodium channel NaVAb as a result of the incorporation of four different IEM mutations in the voltage sensor, which recapitulate the gain-of-function effects observed with these mutations in human NaV1.7. Crystal structures of NaVAb with these IEM mutations revealed that a mutation in the S1 segment of the voltage sensor facilitated the outward movement of S4 gating charges by widening the pathway for gating charge translocation. In contrast, mutations in the S4 segments modified hydrophobic interactions with surrounding amino acid side chains or membrane phospholipids that would enhance the outward movement of the gating charges. These results provide key structural insights into the mechanisms by which these IEM mutations in the voltage sensors can facilitate outward movements of the gating charges in the S4 segment and cause hyperexcitability and severe pain in IEM. Our work gives new insights into IEM pathogenesis at the near-atomic level and provides a molecular model for mutation-specific therapy of this debilitating disease.

British Journal of PharmacologyAlexander et al.Original Research

The Concise Guide to PHARMACOLOGY 2023/24: Ion channels

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands ( https://www.guidetopharmacology.org/ ), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.16178 . Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Cell Reports MethodsEltokhi et al.Original Research

Cell-cycle arrest at the G1/S boundary enhances transient voltage-gated ion channel expression in human and insect cells

Heterologous expression of recombinant ion channel subunits in cell lines is often limited by the presence of a low number of channels at the cell surface level. Here, we introduce a combination of two techniques: viral expression using the baculovirus system plus cell-cycle arrest at the G1/S boundary using either thymidine or hydroxyurea. This method achieved a manifold increase in the peak current density of expressed ion channels compared with the classical liposome-mediated transfection methods. The enhanced ionic current was accompanied by an increase in the density of gating charges, confirming that the increased yield of protein and ionic current reflects the functional localization of channels in the plasma membrane. This modified method of viral expression coordinated with the cell cycle arrest will pave the way to better decipher the structure and function of ion channels and their association with ion channelopathies.

IUPHAR/BPS Guide to Pharmacology CITECatterall et al.Original Research

Voltage-gated sodium channels (NaV) in GtoPdb v.2023.1

Sodium channels are voltage-gated sodium-selective ion channels present in the membrane of most excitable cells. Sodium channels comprise of one pore-forming α subunit, which may be associated with either one or two β subunits [179]. α-Subunits consist of four homologous domains (I-IV), each containing six transmembrane segments (S1-S6) and a pore-forming loop. The positively charged fourth transmembrane segment (S4) acts as a voltage sensor and is involved in channel gating. The crystal structure of the bacterial NavAb channel has revealed a number of novel structural features compared to earlier potassium channel structures including a short selectivity filter with ion selectivity determined by interactions with glutamate side chains [278]. Interestingly, the pore region is penetrated by fatty acyl chains that extend into the central cavity which may allow the entry of small, hydrophobic pore-blocking drugs [278]. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N-terminal domain, a single transmembrane segment and a shorter cytoplasmic domain.The nomenclature for sodium channels was proposed by Goldin et al., (2000) [146] and approved by the NC-IUPHAR Subcommittee on sodium channels (Catterall et al., 2005, [53]).

IUPHAR/BPS Guide to Pharmacology CITECatterall et al.Original Research

Voltage-gated calcium channels (CaV) in GtoPdb v.2023.1

Ca2+ channels are voltage-gated ion channels present in the membrane of most excitable cells. The nomenclature for Ca2+channels was proposed by [131] and approved by the NC-IUPHAR Subcommittee on Ca2+ channels [72]. Most Ca2+ channels form hetero-oligomeric complexes. The α1 subunit is pore-forming and provides the binding site(s) for practically all agonists and antagonists. The 10 cloned α1-subunits can be grouped into three families: (1) the high-voltage activated dihydropyridine-sensitive (L-type, CaV1.x) channels; (2) the high- to moderate-voltage activated dihydropyridine-insensitive (CaV2.x) channels and (3) the low-voltage-activated (T-type, CaV3.x) channels. Each α1 subunit has four homologous repeats (I-IV), each repeat having six transmembrane domains (S1-S6) and a pore-forming region between S5 and S6. Voltage-dependent gating is driven by the membrane spanning S4 segment, which contains highly conserved positive charges that respond to changes in membrane potential. All of the α1-subunit genes give rise to alternatively spliced products. At least for high-voltage activated channels, it is likely that native channels comprise co-assemblies of α1, β and α2-δ subunits. The γ subunits have not been proven to associate with channels other than the α1s skeletal muscle Cav1.1 channel. The α2-δ1 and α2-δ2 subunits bind gabapentin and pregabalin.

Proceedings of the National Academy of SciencesWisedchaisri et al.preclinical

IEM mutations in the S4-S5 linkers of voltage-gated sodium channels create new hydrogen bonds that stabilize the activated state, causing a negative shift in voltage-dependent activation of 12 to 37.5 mV.

IEM mutations in the S4-S5 linkers of NaV1.7 cause hyperexcitability and severe pain by forming new hydrogen bonds that stabilize the activated state of the voltage sensor.

Frontiers in PhysiologyHovey et al.preclinical

Mice with S1700A, STAA, and S1928A mutations exhibited decreased inotropic response to low doses of beta-adrenergic agonist and exacerbated hypertrophy and heart failure in response to transverse aortic constriction.

Phosphorylation of CaV1.2 at C-terminal regulatory sites is crucial for normal cardiac homeostasis, physiological beta-adrenergic response, and adaptation to pressure-overload stress.

Circulation ResearchBaudel et al.preclinical

Diabetic hyperglycemia drives vascular CaV1.2 superclustering and hypercontractility via PKA-dependent phosphorylation.

May identify S1928 as a diabetic vascular target; leaves open human translation and therapeutic validation.

Proceedings of the National Academy of SciencesHovey et al.preclinical

Cotransfection of CaV1.2-FL with RAD caused 75% inhibition of Ba2+ current, which was stimulated and reversed by FSK.

Offers no immediate clinical implications; leaves open whether convergent phosphorylation regulates native cardiac CaV1.2.

eNeuroDjillani et al.Original Research

Synaptotagmin-7 Enhances Facilitation of Cav2.1 Calcium Channels

Voltage-gated calcium channel Ca v 2.1 undergoes Ca 2+ -dependent facilitation and inactivation, which are important in short-term synaptic plasticity. In presynaptic terminals, Ca v 2.1 forms large protein complexes that include synaptotagmins. Synaptotagmin-7 (Syt-7) is essential to mediate short-term synaptic plasticity in many synapses. Here, based on evidence that Ca v 2.1 and Syt-7 are both required for short-term synaptic facilitation, we investigated the direct interaction of Syt-7 with Ca v 2.1 and probed its regulation of Ca v 2.1 function. We found that Syt-7 binds specifically to the α 1A subunit of Ca v 2.1 through interaction with the synaptic-protein interaction (synprint) site. Surprisingly, this interaction enhances facilitation in paired-pulse protocols and accelerates the onset of facilitation. Syt-7α induces a depolarizing shift in the voltage dependence of activation of Ca v 2.1 and slows Ca 2+ -dependent inactivation, whereas Syt-7β and Syt-7γ have smaller effects. Our results identify an unexpected, isoform-specific interaction between Ca v 2.1 and Syt-7 through the synprint site, which enhances Ca v 2.1 facilitation and modulates its inactivation.

Proceedings of the National Academy of SciencesEl-Din et al.preclinical

Autism-associated gating charge mutations in KV7 channels induced pathogenic gating pore currents that severely disrupted action potential generation and repetitive firing in mouse dopamine neurons.

KV7 ASD mutations may cause ionic leak; hypothesis-generating for channel-targeted therapies, requiring in vivo confirmation.

Frontiers in Cellular NeuroscienceCheah et al.Original Research

Sharp-Wave Ripple Frequency and Interictal Epileptic Discharges Increase in Tandem During Thermal Induction of Seizures in a Mouse Model of Genetic Epilepsy

Dravet Syndrome (DS) is a genetic, infantile-onset epilepsy with refractory seizures and severe cognitive impairment. While network level pathophysiology is poorly understood, work in genetic mouse models of DS reveals selective reduction of inhibitory interneuron excitability, a likely mechanism of seizures and comorbidities. Consistent with the critical role of interneurons in timing and recruitment of network activity, hippocampal sharp wave ripples (SPW-R)-interneuron dependent compound brain rhythms essential for spatial learning and memory-are less frequent and ripple frequency is slower in DS mice, both likely to impair cognitive performance. Febrile seizures are characteristic of DS, reflecting a temperature-dependent shift in excitation-inhibition balance. DS interneurons are sensitive to depolarization block and may fall silent with increased excitation precipitating epileptic transformation of ripples. To determine the temperature dependence of SWP-R features and relationship of SPW-R to hippocampal interictal activity, we recorded hippocampal local field potentials in a DS mouse model and wildtype littermate controls while increasing core body temperature. In both genotypes, temperature elevation speeds ripple frequency, although DS ripples remain consistently slower. The rate of SPW-R also increases in both genotypes but subsequently falls in DS mice as interictal epileptic activity simultaneously increases preceding a thermally-evoked seizure. Epileptic events occur intermixed with SPW-R, some during SPW-R burst complexes, and transiently suppress SPW-R occurrence suggesting shared network elements. Together these data demonstrate a temperature dependence of SPW-R rate and ripple frequency and suggest a pathophysiologic mechanism by which elevated temperature transforms a normal brain rhythm into epileptic event.

All publications →

Publications

Nutritional PsychiatryNano et al.Meta-Analysis

Vitamin D deficiency and depressive episodes in adolescents and young adults: systematic review and meta-analysis

IUPHAR/BPS Guide to Pharmacology CITECatterall et al.Original Research

Voltage-gated calcium channels (CaV) in GtoPdb v.2025.3

This analysis reveals the organization of calcium channels, highlighting the structure of α1 subunits and their families.

Journal of Affective Disorders ReportsNano et al.Cross-Sectional Study

“I wish I could work on school stuff.” Investigating the impact of remote learning on undergraduate students’ academic success and mental health during the COVID-19 lockdown

Liu et al.Original Research

Bottom-up design of calcium channels from defined selectivity filter geometry

Journal of Biological ChemistryWang et al.preclinical

Cardiac-selective Rad-/- mice exhibited higher baseline LVEF and basal cardiomyocyte L-type Ca2+ current than Rad+/+ controls, while AKAP-IS peptide completely abolished isoproterenol-induced L-type Ca2+ current upregulation in isolated cardiomyocytes.

Proceedings of the National Academy of SciencesEltokhi et al.Original Research

Pathogenic gating pore current conducted by autism-related mutations in the Na V 1.2 brain sodium channel

Nature CommunicationsTonggu et al.Original Research

Dual receptor-sites reveal the structural basis for hyperactivation of sodium channels by poison-dart toxin batrachotoxin

ChannelsCatterallReview

Voltage gated sodium and calcium channels: Discovery, structure, function, and Pharmacology

The Journal of General PhysiologyWisedchaisri et al.Original Research

Structural basis for severe pain caused by mutations in the voltage sensors of sodium channel NaV1.7

British Journal of PharmacologyAlexander et al.Original Research

The Concise Guide to PHARMACOLOGY 2023/24: Ion channels

Cell Reports MethodsEltokhi et al.Original Research

Cell-cycle arrest at the G1/S boundary enhances transient voltage-gated ion channel expression in human and insect cells

IUPHAR/BPS Guide to Pharmacology CITECatterall et al.Original Research

Voltage-gated sodium channels (NaV) in GtoPdb v.2023.1

IUPHAR/BPS Guide to Pharmacology CITECatterall et al.Original Research

Voltage-gated calcium channels (CaV) in GtoPdb v.2023.1

Proceedings of the National Academy of SciencesWisedchaisri et al.preclinical

IEM mutations in the S4-S5 linkers of voltage-gated sodium channels create new hydrogen bonds that stabilize the activated state, causing a negative shift in voltage-dependent activation of 12 to 37.5 mV.

IEM mutations in the S4-S5 linkers of NaV1.7 cause hyperexcitability and severe pain by forming new hydrogen bonds that stabilize the activated state of the voltage sensor.

Frontiers in PhysiologyHovey et al.preclinical

Mice with S1700A, STAA, and S1928A mutations exhibited decreased inotropic response to low doses of beta-adrenergic agonist and exacerbated hypertrophy and heart failure in response to transverse aortic constriction.

Phosphorylation of CaV1.2 at C-terminal regulatory sites is crucial for normal cardiac homeostasis, physiological beta-adrenergic response, and adaptation to pressure-overload stress.

Circulation ResearchBaudel et al.preclinical

Autism-associated gating charge mutations in KV7 channels induced pathogenic gating pore currents that severely disrupted action potential generation and repetitive firing in mouse dopamine neurons.

KV7 ASD mutations may cause ionic leak; hypothesis-generating for channel-targeted therapies, requiring in vivo confirmation.

Frontiers in Cellular NeuroscienceCheah et al.Original Research

Sharp-Wave Ripple Frequency and Interictal Epileptic Discharges Increase in Tandem During Thermal Induction of Seizures in a Mouse Model of Genetic Epilepsy