William Catterall

• University of Washington

Native ion channels play key roles in biological systems, and engineered versions are widely used as chemogenetic tools and in sensing devices. 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 c...

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...

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 betwee...

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 l...

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, p...

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 activati...

Heterologous expression of recombinant ion channel subunits in cell lines is often limited by the presenceof 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 eitherthymidine or hydroxyurea. This metho...

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 a...

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-...

Gain-of-function mutations in voltage-gated sodium channel NaV1.7 cause severe inherited pain syndromes, including inherited erythromelalgia (IEM). The structural basis of these disease mutations, however, remains elusive. Here, we focused on three mutations that all substitute threonine residues in the alpha-helical S4-S5 intracellular linker that...

The cardiac calcium channel CaV1.2 conducts L-type calcium currents that initiate excitation-contraction coupling and serves as a crucial mediator of β-adrenergic regulation of the heart. We evaluated the inotropic response of mice with mutations in C-terminal phosphoregulatory sites under physiological levels of β-adrenergic stimulation in vivo, a...

Voltage-gated calcium channels are evolutionarily related transmembrane signaling proteins that mediate calcium entry during action potentials and other forms of cellular depolarization in order to trigger neurotransmission, secretion, contraction, gene transcription, and other physiological processes. Calcium channels are the molecular targets for...

Voltage-gated calcium channels mediate calcium entry into cells in response to membrane depolarization. The high-voltage-activated Ca2+ channels that have been characterized biochemically are complexes of a pore-forming α1 subunit of ~200–250 kD, a transmembrane, disulfide-linked complex of α2 and δ subunits, an intracellular β subunit, and in some...

Background: L-type CaV1.2 channels undergo cooperative gating to regulate cell function, although mechanisms are unclear. This study tests the hypothesis that phosphorylation of the CaV1.2 pore-forming subunit α1C at S1928 mediates vascular CaV1.2 cooperativity during diabetic hyperglycemia. Methods: A multiscale approach including patch-clamp e...

The L-type calcium currents conducted by the cardiac CaV1.2 calcium channel initiate excitation-contraction coupling and serve as a key regulator of heart rate, rhythm, and force of contraction. CaV1.2 is regulated by β-adrenergic/protein kinase A (PKA)-mediated protein phosphorylation, proteolytic processing, and autoinhibition by its carboxyl-ter...

Significance Autism spectrum disorder (ASD) adversely impacts >1% of children, causing social interaction deficits, repetitive behaviors, and communication disorders. Genetic analysis of ASD has advanced dramatically through genome sequencing, which has identified >500 genes with mutations in ASD. Mutations in the voltage sensor of the voltage-gate...

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 c...

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targe...

Ca2+ channels are voltage-gated ion channels present in the membrane of most excitable cells. The nomenclature for Ca2+channels was proposed by [127] and approved by the NC-IUPHAR Subcommittee on Ca2+ channels [70]. Most Ca2+ channels form hetero-oligomeric complexes. The α1 subunit is pore-forming and provides the binding site(s) for practically a...

The heartbeat is initiated by voltage-gated sodium channel NaV1.5, which opens rapidly and triggers the cardiac action potential; however, the structural basis for pore opening remains unknown. Here, we blocked fast inactivation with a mutation and captured the elusive open-state structure. The fast inactivation gate moves away from its receptor, a...

Calcium (Ca2+) channels are voltage-gated ion channels present in the membrane of most excitable cells. The nomenclature for Ca2+channels was proposed by [127] and approved by the NC-IUPHAR Subcommittee on Ca2+ channels [70]. Most Ca2+ channels form hetero-oligomeric complexes. The α1 subunit is pore-forming and provides the binding site(s) for pra...

Voltage-gated sodium channel NaV1.5 is responsible for initiating and propagating cardiac action potentials by selectively conducting Na⁺ into cardiomyocytes. Class-I antiarrhythmic drugs target NaV1.5 for treatment of arrhythmias. During the last few years, cryogenic electron microscopy (cryo-EM) has become a powerful technique to determine the st...

Voltage-gated sodium (Na V ) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac Na V 1.5 channels with IC 50 = 11.4 nM. Here we reveal the structure of LqhIII bound to Na V 1.5 at 3.3 Å resolut...

Dravet Syndrome (DS) is a severe childhood epilepsy caused by heterozygous loss-of-function mutations in the SCN1A gene encoding brain type-I voltage-gated sodium channel Nav1.1. DS is a devastating disease that typically begins at six to nine months of age. Symptoms include recurrent intractable seizures and premature death with severe neuropsychi...

Voltage-gated sodium (NaV) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The α-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac NaV1.5 channels with IC50=11.4 nM. Here we reveal the structure of LqhIII bound to NaV1.5 at 3.3 Å resolution by cr...

Electrical signaling was a dramatic development in evolution, allowing complex single-cell organisms like Paramecium to coordinate movement and early metazoans like worms and jellyfish to send regulatory signals rapidly over increasing distances. But how are electrical signals generated in biology? In fact, voltage-gated sodium channels conduct sod...

Voltage-gated sodium channels initiate action potentials in prokaryotes and in many eukaryotic cells, including vertebrate nerve and muscle. Their activation is steeply voltage-dependent, but it is unclear how the voltage sensitivity is set or whether it can be broadly shifted to positive voltages. Here we show that the voltage dependence of activa...

Calcium (Ca2+) channels are voltage-gated ion channels present in the membrane of most excitable cells. The nomenclature for Ca2+channels was proposed by [120] and approved by the NC-IUPHAR Subcommittee on Ca2+ channels [68]. Ca2+ channels form hetero-oligomeric complexes. The α1 subunit is pore-forming and provides the binding site(s) for practica...

Voltage-gated sodium channels initiate electrical signals and are frequently targeted by deadly gating-modifier neurotoxins, including tarantula toxins, which trap the voltage sensor in its resting state. The structural basis for tarantula-toxin action remains elusive because of the difficulty of capturing the functionally relevant form of the toxi...

Transmembrane channels and pores have key roles in fundamental biological processes1 and in biotechnological applications such as DNA nanopore sequencing2–4, resulting in considerable interest in the design of pore-containing proteins. Synthetic amphiphilic peptides have been found to form ion channels5,6, and there have been recent advances in de...

Voltage-gated sodium and calcium channels are evolutionarily related transmembrane signaling proteins that initiate action potentials, neurotransmission, excitation-contraction coupling, and other physiological processes. Genetic or acquired dysfunction of these proteins causes numerous diseases, termed channelopathies, and sodium and calcium chann...

Significance We provide evidence of a mechanistic link between ALS and T2DM. Our data show that a subgroup of ALS-T2DM patients have sera that enhance Ca V 1 channel-mediated Ca ²⁺ influx and exaggerate [Ca ²⁺ ] i . These effects occur because the sera accommodate cytotoxic IgG autoantibodies that immunocapture Ca V α 2 δ1 subunits. As a consequenc...

Voltage-gated sodium channel Nav1.5 generates cardiac action potentials and initiates the heartbeat. Here, we report structures of NaV1.5 at 3.2-3.5 Å resolution. NaV1.5 is distinguished from other sodium channels by a unique glycosyl moiety and loss of disulfide-bonding capability at the NaVβ subunit-interaction sites. The antiarrhythmic drug flec...

The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www....

Dravet syndrome (DS) is a severe early-onset epilepsy associated with heterozygous loss-of-function mutations in SCN1A Animal models of DS with global Scn1a haploinsufficiency recapitulate the DS phenotype including seizures, premature death, and impaired spatial memory performance. Spatial memory requires hippocampal sharp wave ripples (SPW-R), wh...

Calcium (Ca2+) channels are voltage-gated ion channels present in the membrane of most excitable cells. The nomenclature for Ca2+channels was proposed by [110] and approved by the NC-IUPHAR Subcommittee on Ca2+ channels [60]. Ca2+ channels form hetero-oligomeric complexes. The α1 subunit is pore-forming and provides the binding site(s) for practica...

Brevetoxins are produced by dinoflagellates such as Karenia brevis in warm-water red tides and cause neurotoxic shellfish poisoning. They bind to voltage-gated sodium channels at neurotoxin receptor 5, making the channels more active by shifting the voltage-dependence of activation to more negative potentials and by slowing the inactivation process...

Diltiazem is a widely prescribed Ca2+ antagonist drug for cardiac arrhythmia, hypertension, and angina pectoris. Using the ancestral CaV channel construct CaVAb as a molecular model for X-ray crystallographic analysis, we show here that diltiazem targets the central cavity of the voltage-gated Ca2+ channel underneath its selectivity filter and phys...

Study Objectives Sleep disturbances are common co-morbidities of epileptic disorders. Dravet syndrome (DS) is an intractable epilepsy accompanied by disturbed sleep. While there is evidence that daily sleep timing is disrupted in DS, the difficulty of chronically recording polysomnographic sleep from patients has left our understanding of the effec...

Significance Dravet Syndrome is an intractable epileptic disorder that includes cognitive and social-interaction deficits. It is caused by loss-of-function mutations in the brain sodium channel Na V 1.1. We asked whether symptoms of Dravet Syndrome could be induced by introducing the mutation only in the hippocampus, a brain region important for le...

Voltage-gated sodium (NaV) channels initiate action potentials in nerve, muscle, and other electrically excitable cells. The structural basis of voltage gating is uncertain because the resting state exists only at deeply negative membrane potentials. To stabilize the resting conformation, we inserted voltage-shifting mutations and introduced a disu...

Background: Dravet Syndrome (DS) is an epileptic disorder characterized by spontaneous and thermally-induced seizures, hyperactivity, cognitive deficits, autistic-like behaviors, and Sudden Unexpected Death in Epilepsy (SUDEP). DS is caused by de novo loss-of-function mutations in the SCN1A gene. Selective loss of GABAergic interneuron excitabilit...

Activation of Ca V 2.1 voltage-gated calcium channels is facilitated by preceding calcium entry. Such self-modulatory facilitation is thought to contribute to synaptic facilitation. Using knockin mice with mutated Ca V 2.1 channels that do not facilitate (Ca IM-AA mice), we surprisingly found that, under conditions of physiological calcium and near...

Potency of drug action is usually determined by binding to a specific receptor site on target proteins. In contrast to this conventional paradigm, we show here that potency of local anesthetics (LAs) and antiarrhythmic drugs (AADs) that block sodium channels is controlled by fenestrations that allow drug access to the receptor site directly from th...

Homotetrameric bacterial voltage-gated sodium channels share major biophysical features with their more complex eukaryotic counterparts, including a slow-inactivation mechanism that reduces ion-conductance activity during prolonged depolarization through conformational changes in the pore. The bacterial sodium channel Na V Ab activates at very nega...

Stimulation of the L-type Ca ²⁺ current conducted by Ca V 1.2 channels in cardiac myocytes by the β-adrenergic/protein kinase A (PKA) signaling pathway requires anchoring of PKA to the Ca V 1.2 channel by an A-kinase anchoring protein (AKAP). However, the AKAP(s) responsible for regulation in vivo remain unknown. Here, we test the role of the AKAP...

Voltage-gated calcium channels couple depolarization of the cell-surface membrane to entry of calcium, which triggers secretion, contraction, neurotransmission, gene expression, and other physiological responses. They are encoded by ten genes, which generate three voltage-gated calcium channel subfamilies: CaV1; CaV2; and CaV3. At synapses, CaV2 ch...

Potassium-sensitive hypokalaemic and normokalaemic periodic paralysis are inherited skeletal muscle diseases characterized by episodes of flaccid muscle weakness1,2. They are caused by single mutations in positively charged residues ('gating charges') in the S4 transmembrane segment of the voltage sensor of the voltage-gated sodium channel Nav1.4 o...

Activity-dependent regulation controls the balance of synaptic excitation to inhibition in neural circuits, and disruption of this regulation impairs learning and memory and causes many neurological disorders. The molecular mechanisms underlying short-term synaptic plasticity are incompletely understood, and their role in inhibitory synapses remain...

Significance Medicinal cannabis use is booming despite limited preclinical evidence and mechanistic insight. Recent clinical trials of cannabidiol (CBD) in Dravet syndrome (DS) support its clinical efficacy for reduction of seizure frequency and invite study of its benefits for additional DS symptoms. We demonstrate here that treatment with CBD is...

Electrical signals generated by minute currents of ions moving across cell membranes are central to all rapid processes in biology. Initiation and propagation of electrical signals requires voltage-gated sodium (NaV) and calcium (CaV) channels. These channels contain a tetramer of membrane-bound subunits or domains comprising a voltage sensor and a...

Significance Bacterial voltage-gated sodium channels serve as models of their vertebrate counterparts because they have similar functional components in a simpler structure. We present high-resolution structures of tightly closed and open states. In the closed state, the activation gate fully occludes the conduction pathway, and the intracellular C...

The elucidation of high-resolution structures of voltage-gated sodium channels has opened the way to elucidating the mechanism of sodium permeation and selectivity. Molecular simulation studies of bacterial sodium channel NavAb (Chakrabarti et al., PNAS 110, 11331-11336, 2013) suggested that Na+ binding and permeation through the selectivity filter...

The L-type Ca²⁺ channel Cav1.2 controls multiple functions throughout the body including heart rate and neuronal excitability. It is a key mediator of fight-or-flight stress responses triggered by a signaling pathway involving β-adrenergic receptors (βARs), cyclic adenosine monophosphate (cAMP), and protein kinase A (PKA). PKA readily phosphorylate...

Significance Calcium entry initiates contraction in cardiac myocytes, and altered expression of voltage-gated calcium channel 1.2 (Ca V 1.2) causes heart failure in mice. Here we show that reducing β-adrenergic regulation of Ca V 1.2 by mutation of a PKA site in the C-terminal domain causes age-related heart failure. Dual mutation of a nearby casei...

Significance Learning and memory are caused by changes in strength of communication between neurons at synapses. Both brief changes (short-term plasticity) and long-lasting changes (long-term plasticity) are important. Synaptic transmission is initiated by calcium channels, which are regulated by calcium-sensor proteins that induce short-term synap...

Ca(2+) antagonist drugs are widely used in therapy of cardiovascular disorders. Three chemical classes of drugs bind to three separate, but allosterically interacting, receptor sites on CaV1.2 channels, the most prominent voltage-gated Ca(2+) (CaV) channel type in myocytes in cardiac and vascular smooth muscle. The 1,4-dihydropyridines are used pri...

Significance ATP-sensitive potassium (K ATP ) channels are present in cardiac and smooth muscle; when activated, they relax blood vessels and decrease cardiac action potential duration, reducing cardiac contractility. Cantu syndrome (CS) is caused by mutations in K ATP genes that result in overactive channels. Contrary to prediction, we show that t...

Agonist-triggered downregulation of β-adrenergic receptors (ARs) constitutes vital negative feedback to prevent cellular overexcitation. Here, we report a novel downregulation of β2ARsignaling highly specific for Cav1.2. We find that β2-ARbinding to Cav1.2 residues 1923-1942 is required for β-adrenergic regulation of Cav1.2. Despite the prominence...

Significance Information processing in the brain is mediated through synaptic connections between neurons, where neurotransmitter molecules released from presynaptic nerve terminals stimulate postsynaptic cells. Strength of synaptic transmission is increased transiently by short-term synaptic facilitation in response to repeated stimulation of nerv...

Significance Muscle contraction begins with release of neurotransmitter molecules from motor-nerve terminals onto muscle fibers. Strength of contraction depends on high-frequency stimulation of the nerve, which induces short-term increases in neurotransmitter release through presynaptic facilitation. Neurotransmitter release is initiated via calciu...

Regulation of L-type calcium current is critical for the development, function, and regulation of many cell types. CaV1.2 channels that conduct L-type calcium currents are regulated by many protein kinases, but the sites of action of these kinases remain unknown in most cases. We combined mass spectrometry (LC-MS/MS) and whole-cell patch clamp tech...

Voltage-gated sodium channels (NaVs) and calcium channels (CaVs) are involved in electrical signaling, contraction, secretion, synaptic transmission, and other physiological processes activated in response to depolarization. Despite their physiological importance, the structures of these closely related proteins have remained elusive because of the...

Neurological and psychiatric syndromes often have multiple disease traits, yet it is unknown how such multi-faceted deficits arise from single mutations. Haploinsufficiency of the voltage-gated sodium channel Na(v)1.1 causes Dravet syndrome, an intractable childhood-onset epilepsy with hyperactivity, cognitive deficit, autistic-like behaviours, and...

Even though crystallographic structures of several cation channels are known at atomistic resolution, the molecular basis for selective ion permeation, and in particular, the role of structural fluctuations of the channel in that process, remains unclear. The determination of structures of voltage-gated sodium channels opens the way to elucidating...

Significance The heart contracts more forcefully in response to fear, stress, or exercise through the fight-or-flight response. This physiological process is mediated by β-adrenergic receptors acting through adenylyl cyclase, cAMP, and cAMP-dependent protein kinase (PKA), which phosphorylates the cardiac calcium channel Ca V 1.2 and increases its a...

Facilitation and inactivation of P/Q-type Ca2+ currents mediated by Ca2+/calmodulin binding to CaV2.1 channels contribute to facilitation and rapid depression of synaptic transmission, respectively. Other calcium sensor proteins displace calmodulin from its binding site and differentially modulate P/Q-type Ca2 + currents, resulting in diverse patte...

Dominant loss-of-function mutations in voltage-gated sodium channel NaV1.1 cause Dravet Syndrome, an intractable childhood-onset epilepsy. NaV1.1(+/-) Dravet Syndrome mice in C57BL/6 genetic background exhibit severe seizures, cognitive and social impairments, and premature death. Here we show that Dravet Syndrome mice in pure 129/SvJ genetic backg...

Voltage-gated sodium channels mediate the initiation and propagation of action potentials in excitable cells. Transmembrane segment S4 of voltage-gated sodium channels resides in a gating pore where it senses the membrane potential and controls channel gating. Substitution of individual S4 arginine gating charges (R1-R3) with smaller amino acids al...

Significance Dravet syndrome (DS) is an intractable childhood epilepsy syndrome accompanied by mental disability, behaviors similar to autism, and premature death. DS is caused by dominant loss-of-function mutations in the gene encoding the Na V 1.1 sodium channel, SCN1A , which initiates electrical signals in the nerve cells of the brain. The phys...

L-type voltage-gated Ca(2+) channels (LTCC) couple neuronal excitation to gene transcription. LTCC activity is elevated by the cyclic AMP (cAMP)-dependent protein kinase (PKA) and depressed by the Ca(2+)-dependent phosphatase calcineurin (CaN), and both enzymes are localized to the channel by A-kinase anchoring protein 79/150 (AKAP79/150). AKAP79/1...

Autism spectrum disorder (ASD) may arise from increased ratio of excitatory to inhibitory neurotransmission in the brain. Many pharmacological treatments have been tested in ASD, but only limited success has been achieved. Here we report that BTBR T(+)Itpr3(tf)/J (BTBR) mice, a model of idiopathic autism, have reduced spontaneous GABAergic neurotra...

The CaV1.1 and CaV1.2 voltage-gated calcium channels initiate excitation-contraction coupling in skeletal and cardiac myocytes, excitation-transcription coupling in neurons, and many other cellular processes. Up-regulation of their activity by the β-adrenergic-PKA signaling pathway increases these physiological responses. PKA up-regulation of CaV1....

Multiple cAMP phosphodiesterase (PDE) isoforms play divergent roles in cardiac homeostasis, but the molecular basis for their non-redundant function remains poorly understood. Here we report a novel role for the PDE4B isoform in β-adrenergic (βAR) signaling in the heart. Genetic ablation of PDE4B disrupts βAR-induced cAMP transients measured by FRE...

The determination of a high-resolution 3D structure of voltage-gated sodium channel NaVAb opens the way to elucidating the mechanism of ion conductance and selectivity. To examine the selective permeation of Na+ over K+ through the selectivity filter of the channel, we performed large-scale molecular dynamics simulations of NaVAb in an explicit, hy...

Voltage-gated calcium (CaV) channels catalyse rapid, highly selective influx of Ca(2+) into cells despite a 70-fold higher extracellular concentration of Na(+). How CaV channels solve this fundamental biophysical problem remains unclear. Here we report physiological and crystallographic analyses of a calcium selectivity filter constructed in the ho...

Significance This work defines the in vivo role of phosphorylation of Ser1700 and Thr1704 in Ca V 1.2 channels in the fight-or-flight response. Mutation of both residues to Ala in STAA mice reduced basal L-type Ca ²⁺ currents and markedly decreased β-adrenergic stimulation of Ca ²⁺ currents and cell contraction. STAA ventricular myocytes exhibited...

Voltage-gated sodium channels are responsible for the rising phase of the action potential in cardiac muscle. Previously, both TTX-sensitive neuronal sodium channels (NaV1.1, NaV1.2, NaV1.3, NaV1.4 and NaV1.6) and the TTX-resistant cardiac sodium channel (NaV1.5) have been detected in cardiac myocytes, but relative levels of protein expression of t...

Dravet Syndrome (DS) is an intractable genetic epilepsy caused by loss-of-function mutations in SCN1A, the gene encoding brain sodium channel Nav 1.1. DS is associated with increased frequency of sudden unexpected death in humans and in a mouse genetic model of this disease. Here we correlate the timing of declining expression of the murine embryon...