Steve Heinemann, one of the founders of 21st century neuroscience, died on August 6, 2014. To those who had the honor to know him, “Stevie” was a man of personal and professional generosity, contagious energy, scientific integrity, and genuine enthusiasm. His death is a profound loss for all.

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Stephen F. Heinemann (1939–2014). Image courtesy of Joe Belcovson (The Salk Institute, La Jolla, CA).

Steve Heinemann’s arc as a scientist traced that of modern neuroscience overall. Having earned a PhD from Harvard, followed by postdoctoral stints at the Massachusetts Institute of Technology and Stanford, Steve was one of a cadre of young bacteriophage geneticists who in the early 1970s decided to apply biochemistry and molecular biology to the study of nervous system development and function. Starting his own research group at The Salk Institute, where he spent the entirety of his career, Steve, like several of his contemporaries, adopted the neuromuscular junction as a tractable model synapse. This was a stand-in (or so it was believed at the time) for synapses in the brain. Whereas some studied the neuromuscular junction in frogs or electric rays (the electric organ of Torpedo californica is a modified muscle), Steve analyzed the mammalian junction. An important focus of this work was the receptor for the neurotransmitter acetylcholine. Released from the terminals of motor neurons, acetylcholine was known to bind to a receptor on the muscle membrane, open ion channels, depolarize the postsynaptic cell, and thereby induce muscle contraction. However, the molecular identity of the acetylcholine receptor (AChR), and that of pharmacologically related receptors in the central nervous system, were unknown. Indeed, we knew the structure of no ion channel.

Working together with Dave Schubert, Jim Patrick, and others, Steve was able to reproduce and analyze many features of neuromuscular synaptogenesis in culture, to generate antibodies to the muscle AChR, and to uncover the basis of the autoimmune neuromuscular disease myasthenia gravis. However, Steve and his colleagues were most interested in applying recently developed molecular cloning methods to the isolation of cDNAs encoding the muscle AChR, and to thereby know its structure and understand its mode of action.

Although they published a cDNA clone encoding the γ-subunit of the Torpedo AChR, the Heinemann group was largely outpaced by Shosaku Numa and his colleagues, who cloned cDNAs for five different Torpedo subunits (the muscle receptor is a pentamer composed of two α-subunits, and one each of β, γ, and δ or ε). Undeterred, and guessing that the pharmacologically distinct central nervous system receptors must nonetheless be structurally related to muscle AChRs, Jim Boulter, Jim Patrick, and Steve used low-stringency hybridization methods with a mouse muscle α-subunit clone to isolate the first neural AChR subunit, now designated α3. This opened the floodgates, and over the course of the next few years a group of capable students and postdoctoral fellows in the Patrick and Heinemann laboratories cloned and analyzed a slew of α and β AChR subunits from the brain, including some that were highly specialized to function in specific cells, such as the hair cells of the inner ear. These efforts nucleated an entire field, and demonstrated that neural AChRs are in fact part of a larger superfamily of ligand-gated ion channels that also includes receptors for the inhibitory neurotransmitters GABA and glycine, and one form of the receptor for serotonin.

Although acetylcholine is the agent that drives muscle contraction, glutamate is the major excitatory neurotransmitter in the vertebrate central nervous system. Pharmacological studies had shown that glutamate evokes “fast” synaptic responses by acting at three broad classes of cation-selective channels, representing kainate, AMPA, and NMDA subtypes. Furthermore, phenomena such as long-term potentiation in the hippocampus were known to involve activation and modulation of glutamate-gated ion channels, making these receptors high-value targets for those interested in parsing the molecular bases of synaptic plasticity, learning, and memory. It is in this arena that Steve and his group, spearheaded by Michael Hollmann, landed their biggest catch, by being the first researchers to clone a glutamate receptor (now classified as an AMPA subtype) from rat brain. This was truly a watershed moment in the molecular genetic analysis of excitatory transmission in the mammalian brain, and a springboard for elucidating roles for multiple glutamate receptors in synaptic transmission, neural plasticity, and neurological and neuropsychiatric disease. The physiology of these molecules, first identified and analyzed in the Heinemann group, now drives the research efforts of many laboratories.

Steve was a remarkable figure apart from his science. He cofounded the Molecular Neurobiology Laboratory at the Salk Institute, whose successes were in no small part responsible for the Salk’s stellar reputation for neuroscience research during his tenure. Never svelte (at least as we knew him), Steve was nonetheless an avid sportsman. He loved hiking in the Baja backcountry and was an agile competitor on the tennis court and the softball field. He was also a raconteur nonpareil, albeit one prone to embellishment: colleagues at the Salk designated the “Heinemann” as a unit of exaggeration, but this proved to be such a large quantity that everyday hyperbole was more commonly measured in milli-Heinemanns.

Steve and Ann, his wife of 54 years, are parents to five children, and Steve was a big-hearted scientific father to more than 100 trainees now distributed throughout the world. This extended family, and all in the greater neuroscience community who knew him and were influenced by his work, mourn the passing of a true original.