Raymond Dingledine | |
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Born | Celina, Ohio, U.S. | December 17, 1948
Education | |
Occupations |
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Known for | Glutamate receptor biology; neuroinflammation |
Children | 2, including Roger |
Medical career | |
Field | Neuroscience, Neurology |
Institutions | Emory University School of Medicine |
Raymond J Dingledine (born December 17, 1948) is an American pharmacologist and neurobiologist who has made considerable contributions to the field of epilepsy. He serves as Professor in the School of Medicine at Emory University, Atlanta GA, where he chaired the pharmacology department for 25 years and served as Executive Associate Dean of Research for 10 years. [1]
Dingledine grew up in St. Marys, Ohio, a small town bordering Grand Lake St. Marys. He graduated from Michigan State University with a B.S. in biochemistry in 1971, and from Stanford University with a PhD in pharmacology in 1975. His PhD training was under Avram Goldstein. [2] He then did postdoctoral stints with John Kelly and Leslie Iversen in Cambridge UK, and Per Andersen in Oslo Norway. It was in Per’s lab, working with Leif Gjerstad and Iver Langmoen, that he developed a lifelong interest in epilepsy. [2]
Dingledine joined the Department of Pharmacology at the University of North Carolina Chapel Hill in 1978 as an Assistant Professor, rising to full Professor by 1989. Shortly after a sabbatical year at the Salk Institute in Steve Heinemann’s lab, he joined Emory University in 1992 as Chair of the Department of Pharmacology, a job he held until 2017. He also served as Executive Associate Dean of Research in the School of Medicine from 2004-2005 and 2008–2015. [1]
He has served in professional science-intensive organizations throughout his career. He served on the Program Advisory Committee of the Morehouse School of Medicine Neuroscience Institute from its inception in 1997 through 2021, chairing this committee for 14 years. He served the Society for Neuroscience in numerous functions including Treasurer in 2003 and, most recently, as Chair of their Investment Committee for 15 years. At the American Epilepsy Society he chaired the Epilepsy Benchmark Stewards from 2017-2018. From 1995 to 2000, he served as editor-in-chief of Molecular Pharmacology, a major journal sponsored by the American Society for Pharmacology and Experimental Therapeutics. Dingledine co-founded two small pharma companies. NeurOp Inc was founded in 2003 and is currently a clinical-stage company focused on developing NMDA receptor modulators for cerebral ischemia, pain and depression. He serves on NeurOp’s Board of Directors and Scientific Advisory Board. [3] Pyrefin Inc was founded in 2019 to develop novel anti-inflammatory drugs to combat cognitive decline and post-operative pain; he chairs Pyrefin’s Board of Directors. [4] He is an inventor of record for 10 awarded US patents.
His early research focused on the modulation of glutamate receptor-mediated synaptic transmission. [5] During this period he and his team discovered that glycine is a coagonist rather than modulator of NMDA receptors, [6] that shrinkage of extracellular space mediates the transition between interictal and ictal states in the high potassium model of seizures, [7] [8] that a single amino acid residue controls calcium permeation in glutamate receptor channels, [9] and that ifenprodil analogs inhibit NMDA receptors by increasing the sensitivity of receptors to proton inhibition. [10] His current research focuses on the myriad roles of neuroinflammation in neurologic disorders. [11] He demonstrated a profound role for EP2 receptor activation by prostaglandin E2 in COX-2 related pathologies. [12] His work highlights the importance of neuroinflammation in epilepsy.
Dingledine was elected to the US National Academy of Medicine in 2010, [13] the Norwegian Academy of Science and Letters in 2018, [14] and the National Academy of Inventors in 2022. [15] He was elected as a Fellow of the American Association for Advancement of Science in 2003, and a Fellow of the American Society for Pharmacology and Experimental Therapeutics in 2020. [16] His early career was profiled in Nature Medicine in 2002. [2] He received the Bristol-Myers Squibb Neuroscience Award in 1989 and again in 1993, the epilepsy basic research award from the American Epilepsy Society in 1995, a Javits Neuroscience Award from the National Institute of Neurological Disorders and Stroke in 1998, the PhRMA Foundation Career Award in Excellence in 1999, and the Robert R Ruffolo Career Achievement Award from the American Society of Pharmacology and Experimental Therapeutics in 2018. [17] Two endowed prizes have been established in his name, the Ray Dingledine Award for Extraordinary Graduate Achievement in 2018 [18] and the Ray Dingledine Research Impact Award in Pharmacology & Chemical Biology (2019). [19] In 2023, he was awarded the inaugural AMSPC Award in Pharmacology Research and Administration from the Association of Medical School Pharmacology Chairs (AMSPC) [20] and the Axelrod Prize from the Society for Neuroscience.
Dingledine has two sons, Brian and Roger. Dingledine has grown bonsai trees since 1971 and for many years was an avid swimmer with a local Master’s group. He competed in the relay division of the Tugaloo Triathlon and his team (3 Stooges) took first place in 2001, 2003 and 2005, [21] thereby serving as Georgia state champions.
N-methyl-D-aspartic acid or N-methyl-D-aspartate (NMDA) is an amino acid derivative that acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor. Unlike glutamate, NMDA only binds to and regulates the NMDA receptor and has no effect on other glutamate receptors. NMDA receptors are particularly important when they become overactive during, for example, withdrawal from alcohol as this causes symptoms such as agitation and, sometimes, epileptiform seizures.
The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a "coincidence detector" and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate receptors such as the NMDA receptor or AMPA receptor encounter excessive levels of the excitatory neurotransmitter, glutamate, significant neuronal damage might ensue. Excess glutamate allows high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA. In evolved, complex adaptive systems such as biological life it must be understood that mechanisms are rarely, if ever, simplistically direct. For example, NMDA in subtoxic amounts induces neuronal survival of otherwise toxic levels of glutamate.
Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.
Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from the algae Digenea simplex. They have been traditionally classified as a non-NMDA-type receptor, along with the AMPA receptor. KARs are less understood than AMPA and NMDA receptors, the other ionotropic glutamate receptors. Postsynaptic kainate receptors are involved in excitatory neurotransmission. Presynaptic kainate receptors have been implicated in inhibitory neurotransmission by modulating release of the inhibitory neurotransmitter GABA through a presynaptic mechanism.
Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation.
The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.
Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.
Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that are activated by the neurotransmitter glutamate. They mediate the majority of excitatory synaptic transmission throughout the central nervous system and are key players in synaptic plasticity, which is important for learning and memory. iGluRs have been divided into four subtypes on the basis of their ligand binding properties (pharmacology) and sequence similarity: AMPA receptors, kainate receptors, NMDA receptors and delta receptors.
NMDA receptor antagonists are a class of drugs that work to antagonize, or inhibit the action of, the N-Methyl-D-aspartate receptor (NMDAR). They are commonly used as anesthetics for humans and non-human animals; the state of anesthesia they induce is referred to as dissociative anesthesia.
Glutamate [NMDA] receptor subunit epsilon-1 is a protein that in humans is encoded by the GRIN2A gene. With 1464 amino acids, the canonical GluN2A subunit isoform is large. GluN2A-short isoforms specific to primates can be produced by alternative splicing and contain 1281 amino acids.
Glutamate [NMDA] receptor subunit zeta-1 is a protein that in humans is encoded by the GRIN1 gene.
Midafotel is a potent, competitive antagonist at the NMDA receptor. It was originally designed as a potential therapy for excitotoxicity, epilepsy or neuropathic pain. It looked very promising in in vitro trials proving to be a potent competitive antagonist at the NMDA without affecting other receptors. Research continued through to in vivo cat studies where it proved to limit damage after occluding the middle cerebral artery, leading to ischaemia. It also blocked photosensitive epilepsies in baboons.
CGP-37849 is a competitive antagonist at the NMDA receptor. It is a potent, orally active anticonvulsant in animal models, and was researched for the treatment of epilepsy. It also has neuroprotective activity and shows antidepressant and anxiolytic effects.
A convulsant is a drug which induces convulsions and/or epileptic seizures, the opposite of an anticonvulsant. These drugs generally act as stimulants at low doses, but are not used for this purpose due to the risk of convulsions and consequent excitotoxicity. Most convulsants are antagonists at either the GABAA or glycine receptors, or ionotropic glutamate receptor agonists. Many other drugs may cause convulsions as a side effect at high doses but only drugs whose primary action is to cause convulsions are known as convulsants. Nerve agents such as sarin, which were developed as chemical weapons, produce convulsions as a major part of their toxidrome, but also produce a number of other effects in the body and are usually classified separately. Dieldrin which was developed as an insecticide blocks chloride influx into the neurons causing hyperexcitability of the CNS and convulsions. The Irwin observation test and other studies that record clinical signs are used to test the potential for a drug to induce convulsions. Camphor, and other terpenes given to children with colds can act as convulsants in children who have had febrile seizures.
James O. McNamara is an American neurologist and neuroscientist, known for his research of epileptogenesis, the process underlying development and progression of epilepsy. He is the Duke School of Medicine Professor of Neuroscience in the Departments of Neurobiology, Neurology, and Pharmacology and Cancer Biology at Duke University. He served as chair of the Department of Neurobiology at Duke from 2002 to 2011
Stephen F. Heinemann (1939–2014) was a professor of neuroscience at the Salk Institute. He was an early researcher in the field of molecular neuroscience, contributing to the current knowledge of how nerves communicate with each other, and the role of neurotransmitters. Stephen Heinemann died August 6, 2014, of kidney failure.
R. Suzanne Zukin is an American neuroscientist and a professor of neuroscience who directs a research lab as a F. M. Kirby Chair in Neural Repair and Protection and director of the Neuropsychopharmacology Center at Albert Einstein College of Medicine. Zukin's areas of research include neurodegenerative disorders, Ischemia, Epigenetics and Autism and uses molecular biology approaches to research these disorders. Zukin has made seminal contributions to the understanding of NMDA and AMPA receptor function and activity.
Willardiine (correctly spelled with two successive i's) or (S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione is a chemical compound that occurs naturally in the seeds of Mariosousa willardiana and Acacia sensu lato. The seedlings of these plants contain enzymes capable of complex chemical substitutions that result in the formation of free amino acids (See:#Synthesis). Willardiine is frequently studied for its function in higher level plants. Additionally, many derivates of willardiine are researched for their potential in pharmaceutical development. Willardiine was first discovered in 1959 by R. Gmelin, when he isolated several free, non-protein amino acids from Acacia willardiana (another name for Mariosousa willardiana) when he was studying how these families of plants synthesize uracilyalanines. A related compound, Isowillardiine, was concurrently isolated by a different group, and it was discovered that the two compounds had different structural and functional properties. Subsequent research on willardiine has focused on the functional significance of different substitutions at the nitrogen group and the development of analogs of willardiine with different pharmacokinetic properties. In general, Willardiine is the one of the first compounds studied in which slight changes to molecular structure result in compounds with significantly different pharmacokinetic properties.
Stephanie Schorge is a Professor of Neuroscience in the Department of Neuroscience, Physiology and Pharmacology at University College London. She is known for her research into mutations that cause neurological diseases.