William A. Catterall (1946–2024)
Authors: Todd Scheuer, Ruth Westenbroek, Ning Zheng, Franck Kalume, Thuy N. Vien, Jian Payandeh, Paul G. DeCaen
Journal: Neuron (2024)

William A. Catterall, Ph.D., a luminary figure in the fields of neuroscience and ion channel biophysics, passed away suddenly on February 28 at age 77. He was a fearless and dedicated scientist, mentor, leader, and educator whose monumental scientific achievements uncovered the chemical basis of electrical signaling in neurons and other excitable cells. Bill was born October 12, 1946, in Providence, Rhode Island. From modest beginnings, he attended Brown University on a scholarship, earning a B.S. in chemistry, and he went on to receive his Ph.D. in physiological chemistry from Johns Hopkins University. He trained with Nobel Laureate Marshall Nirenberg at the NIH before joining the Department of Pharmacology at the University of Washington in 1977. He quickly climbed the ranks and became a full professor in 1981 before becoming department chair in 1983—a position he relinquished in 2016. Bill emphasized choosing important scientific questions in academic research. As a young postdoctoral fellow at the NIH, Bill chose what would be his lifelong investigation of voltage-gated sodium and calcium channels, which mediate rapid action potential signaling in neurons and cardiomyocytes. Bill correctly hypothesized that elucidating the chemical dysfunction of these channels would unlock their therapeutic potential for treating human conditions, including neurological disorders and cardiac arrhythmias. At that time, biophysicists were beginning to understand their function as biological transistors, but the molecules responsible for creating the ion-conducting channel across cell membranes were unidentified. His early studies pioneered the identification, purification, and characterization of voltage-gated sodium channel proteins. Using ion flux and neurotoxin binding to neuroblastoma cells, Bill discovered sodium channels had at least three independent, but allosterically linked, neurotoxin receptor sites. Over the first decade of his career at the University of Washington, Bill's lab elegantly used the natural affinity of scorpion toxins and photoaffinity labeling to biochemically identify the pore forming alpha and beta subunits that comprise the sodium channel complex, findings which would be later fully validated and serve as the basis of their biological assemblies. Bill's lab was the first to isolate sodium channel proteins using tritiated saxitoxin to track them and reconstitute their function from purified components. At the time, sodium channels were not thought to be subject to regulation, but sites for phosphorylation by cAMP-dependent protein kinase (PKA) were found, leading to subsequent studies of regulation by these and other kinases. Bill was quick to identify and embrace new advances in all fields of biological sciences. At a time when researchers often stayed confined to their core technical expertise, Bill fearlessly adopted protein sequencing, protein synthesis, antibody generation, and molecular biological techniques. Using these advanced methods, Bill elucidated the first channel receptor sites and resolved their complex stochiometric assemblies—features he would later revisit and define with atomic detail. Bill pioneered functional studies through heterologous channel expression and added whole-cell voltage-clamp electrophysiology to the lab's repertoire, and he used these techniques to discover the inactivation gate and other sites of channel regulation. The findings provided the blueprints to investigate their role in brain development, pharmacology, and dysfunction in various disease pathologies. Genetic mutations in ion channels result in a variety of human diseases. Using his keen insights into their molecular regulation, Bill developed several important mouse models to study disease-causing mutations in sodium channel genes. Key among them was a mouse model of Dravet Syndrome—a severe epilepsy that is caused by haploinsufficiency of a neuronal sodium channel subtype. Bill's love for sodium channels was only matched by his passion for calcium channels. These channels are required for coupling membrane depolarization to calcium entry, which drives contraction, secretion, neurotransmission, and gene expression in the cells of various tissues. Bill's biochemical strategies led to the identification and purification of essential calcium channel subunits and the stoichiometry of their native complexes. In the heart, studies showed that these channels are subject to intricate phosphorylation regulatory mechanisms, which modulate their activity in response to various physiological cues, such as the fight or flight response. In the brain, Bill's work detailed molecular interactions linking presynaptic calcium channels to neurotransmitter release. Further studies probed their modulation by interactions with G protein subunits and calcium-binding proteins, findings that cemented their central role in Ca2+-mediated signal transduction and cell physiology. The foundational biochemical findings of his early career foreshadowed a crowning achievement that was reached decades later—the high-resolution determination of multiple sodium and calcium channel structures by X-ray crystallography and cryo-electron microscopy. In conjunction with electrophysiology and molecular modeling, these collaborative structural studies revealed the molecular basis for many properties of these channels, including the selectivity of sodium over other cations, determination of antiarrhythmic and anesthetic drug binding sites, and the mechanisms underlying the conformational changes that shift the channel to conductive states. These studies gave credence to Bill's previously proposed "sliding helix" model of voltage sensor function based on thermodynamic considerations. They also structurally defined the sites of toxin interactions with these channels and their mechanisms of action. Bill was thrilled and energized by these breakthrough studies, which were achieved in the final decades of a 40-year-plus scientific career. Based on these contributions and his fearless leadership, and on the talent and hard work of his trainees and collaborators, Bill received nearly every major scientific accolade. He was elected to the National Academy of Sciences (1989), to the National Academy of Medicine (2000), as a Fellow of the American Academy of Arts and Sciences (2000), to the Royal Society London (2008), as a Fellow of the American Association for the Advancement of Science (2009), and as a Fellow of the American Society for Pharmacology and Experimental Therapeutics (2019) for his seminal contributions to the fields of physiology, pharmacology, and neuroscience. In 2010, he was a recipient of the prestigious Canada Gairdner Award for his groundbreaking research on the underlying molecular causes of epilepsy and heart disease. Bill was awarded the Robert R. Ruffolo Career Achievement Award in Pharmacology from the American Society of Pharmacology and Therapeutics in 2016 and a Lifetime Achievement Award from the International Union of Pharmacologists in 2023, to name just a few. While proud of this recognition, Bill remained scientifically hungry and regularly published in high-impact journals and pushed the field forward until his untimely death. Bill's success relied on the research community he built. His reputation recruited trainees from all over the US and from 20 foreign countries, which fostered a unique social and collaborative environment within the laboratory. Bill had an uncanny ability to identify smart, industrious, and fun-loving lab members who formed an ever-evolving and irreverent scientific family. Bill was intentional about developing community. Annual multi-day lab hikes introduced members from disparate backgrounds to the outdoors and the beauty of the Pacific Northwest. In addition to their scientific activities, lab members camped and skied together—activities that included each other's families as a motley tribe of "Catterallians." Bill loved tradition and would organize annual barbeques, holiday parties, and farewell events for lab members who received signed posters of the Seattle skyline and an infamous pen set commemorating their time in the lab. Among his trainees, Bill had several nicknames, such as "Wild Bill" and "B-Cat," which reflected his personality and spirit. He had ambitious standards and had similar expectations for his trainees. They often considered him a tough mentor and sometimes even unreasonable, but many eventually grew to appreciate those expectations. As a voracious reader of scientific literature and a former member of a college debate team, Bill was a formidable force and persuasive voice when engaged in scientific deliberations. Beyond their scientific development, trainees developed deep personal and professional relationships that extend around the globe. Bill's relentless efforts training young scientists has resulted in a legacy of Catterall lab alumni that are influential in scientific leadership roles in academia and industry, worldwide. Bill served as chair of the University of Washington Department of Pharmacology for more than 30 years. He was diligent in his advocacy for the department and renowned for his cultivation of an environment of rigorous graduate school training and faculty research excellence. By recruiting outstanding faculty with interests in multiple fields, the department was highly regarded under his leadership. Bill was committed to teaching and helped establish an undergraduate program in neurobiology at the University of Washington. He was a masterful lecturer, a skill that shined through, whether in the classes he taught or as a sought-after presenter at major scientific meetings. In addition to his departmental responsibilities, Bill served in diverse leadership roles throughout the university and in the broader scientific community. He served on national governing boards of a range of scientific societies, on journal editorial boards (including that of Neuron), and on external scientific advisor committees of private entities such as the Howard Hughes Medical Institute. In each of these roles Bill gave the same diligence, dedication, and energy that he poured into his research work. Bill lived life fully. He loved to ski and travel, sometimes in conjunction with his scientific work. He was a frequent presenter at the Winter Conference on Brain Research. As a consummate learner and educator, he would eagerly share what he learned about the history and culture of the places he visited. Bill had a lifelong love of sailing, and each summer he took weekend to weeklong sailing trips to the islands of the Puget Sound. Most mornings found him at the Intramural Activity Center of the University of Washington for a daily swim. He was a devotee of the symphony, the opera, and major league baseball. He always loved competition and would occasionally make a friendly wager with former lab members. He enjoyed tasty food and fine wine. High points for Bill and his wife, Tina, were two sabbaticals in Southern France. Bill had a large cadre of friends, both scientific and personal, who, along with his wife, children, and grandchild, made his life richer. Indeed, Bill's career was remarkably productive and will be remembered for its longevity—spanning over 4 decades of NIH grant funding, thousands of citations, hundreds of manuscripts, and the mentorship of numerous trainees, leaving a legacy that will extend far beyond his scientific achievements. Bill lived by the belief that you are not defined by your setbacks, but rather, how you handle them. His life embodied a relentless mentality of always moving forward, both scientifically and personally, even in the wake of unforeseen events. Our memory of Bill's ethos, achievements, and character inspires and reminds us to move fearlessly toward the next chapter in all phases of our lives.