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Dr Nancy J Leidenheimer hopes to understand the processes of neurotransmitter receptor formation and trafficking. Here, she discusses her interests, her research and the promise of its therapeutic application understand brain function. Computers will be the key to storing, processing and integrating vast amounts of information, as well as to modelling and mapping the brain’s circuitry. Despite incredible advances in neuroscience, these findings have yet to translate into effective treatments for many neurological disorders and psychiatric conditions. Thus, while unravelling the complexities of the brain and its dysfunction will be a key to treating devastating brain disorders, there will likely be a long time lag between understanding these disorders and the application of clinically effective treatments. What key challenges do you face in your work? What excites you most about cellular neuroscience? The unimaginable complexity of nerve cells is fascinating. Neurons have elaborate morphologies, dynamic function and unbelievably complex regulatory mechanisms. We are still at the point where we understand only a small fraction of what is knowable; the brain has roughly 100 billion neurons that are interconnected by 100 trillion synapses. One of the most tantalising questions is how cellular complexity translates into thought and mood. The answer to this mystery is beginning to be revealed thanks in part to technological advancements such as those in the neuroimaging field. It has been a privilege to watch the field of neuroscience unfold. Do you believe the complex mysteries of the brain will ever be completely unravelled? The brain is the last frontier in understanding human physiology. Whether the mind is capable of understanding itself is an intriguing question. Hopefully, the technological advances of the past few decades will allow us to go beyond the brain’s capacity, permitting us to thoroughly Oddly, the biggest challenge we face is the lack of cell biology knowledge pertinent for understanding how γ-aminobutyric acid (GABA) chaperones the GABAA receptor. It turns out that the chaperoning story is an elaborate one that likely involves a number of other proteins and processes about which little is known. For example, we now know that GABA is found in the endoplasmic reticulum. We do not know how it gets inside this cell organelle but assume it is transported there by a protein. Because it has been known for decades that GABA is present inside mitochondria, a cell organelle involved in energy metabolism, we looked to the scientific literature to see how GABA enters mitochondria. Surprisingly, this mechanism remains unknown in animal cells, but was recently discovered for plant cell mitochondria. Thus, the clues we gather, and hypotheses we formulate, are being pieced together from limited scientific information that has us delving into diverse scientific literature. While this substantially broadens the scope of our research and slows progress, it keeps things interesting. Another challenge we face is scepticism. It is difficult for some to consider that a neurotransmitter may have a function beyond the synapse, especially as a chaperone within DR NANCY J LEIDENHEIMER Regulating receptors the endoplasmic reticulum. A certain amount of scepticism, however, is healthy for keeping science in check. Lastly, a challenge facing biomedical science is the contraction of National Institutes of Health (NIH)-funded research, which could have a long-term negative impact on the scientific enterprise. Could you discuss the promise of pharmacological chaperones as an approach for the treatment of disorders that result from protein misfolding? My colleague Henry Lester (Cal Tech) and I recently guest-edited a special issue of the journal Pharmacological Research. This edition, entitled Pharmacological Chaperones: On the Frontier of 21st Century Therapeutics highlights the numerous proteins that undergo pharmacological chaperoning, and the potential of pharmacological chaperones as therapeutic agents for a spectrum of diseases. While gene therapy has been widely considered for the correction of genetic disorders, including those diseases resulting from protein misfolding, the road has been long and uncertain. Pharmacological chaperones appear to be a promising and, in some respects, more practical approach for the treatment of genetic disorders in which mutated misfolded proteins can be coaxed to fold correctly. One of our currently funded projects focuses on using pharmacological chaperones to ‘rescue’ epilepsy-associated GABAA receptor mutants that are not properly folded. Looking ahead, what direction will your research take? For now, our finding that the neurotransmitter GABA acts as chaperone to facilitate GABAA receptor biogenesis raises numerous questions that will take years to address. We are also beginning a drug discovery programme. It is possible that, if successful, this new aspect of our programme may lead us in a translational direction. WWW.RESEARCHMEDIA.EU 127 DR NANCY J LEIDENHEIMER Unfolding the mysteries of neurotransmitter receptor biogenesis Ongoing research at Louisiana State University Health Sciences Center Shreveport aims to better understand the formation of neurotransmitter receptors and is providing new insights into previously underappreciated mechanisms of receptor biogenesis. These insights may translate into the development of a novel treatment avenue for certain neurological and psychiatric disorders NEURONS ARE NOT static entities, but instead highly dynamic transducers of chemical signalling molecules called neurotransmitters. The process whereby neurons exchange information between each other is called neurotransmission. This remarkable feat is achieved through membrane bound neurotransmitter receptors that bind neurotransmitters with high specificity. The brain utilises a variety of neurotransmitter/ neurotransmitter receptor partners. The activation of neurotransmitter receptors by their neurotransmitters leads to either brain excitation or inhibition. For example, the predominant inhibitory neurotransmitter receptor of the brain, the GABAA receptor, is highly specific for its ligand, γ-aminobutyric acid (GABA), from which it derives its name. Neurotransmitter receptors are mostly found at the synapse – the specialised structure, at which neurotransmitter is released from one neuron onto the neurotransmitter receptor of an adjacent neuron. When the receptor is activated by a neurotransmitter, biochemical and/or electrical changes occur in the receiving neuron leading to either 128 INTERNATIONAL INNOVATION inhibition or excitation. In the case of the GABAA receptor, activation leads to an increase in chloride conductance, hyperpolarisation and neuronal inhibition. changes in neurotransmission at the synapse, becoming either stronger or weaker depending on the context. RECEPTOR BIOGENESIS The GABAA receptor represents an extremely important therapeutic target due to its central role in maintaining neuronal inhibition At the level of neurons and networks, the precise consequences of neurotransmission depend on the type of receptor present, the number of receptors and their spatial location. Principally because of this, changes at the receptor level can significantly impact the function of neurons and the networks they are part of. A good example of this are the mechanisms underlying learning and memory, which fundamentally depend upon Receptors are proteins that need to be folded into very specific shapes, or conformations. Since the number of theoretically possible conformations a given protein can form can be impossibly large, active mechanisms are required for achieving the correct conformation. According to Levinthal’s paradox, if even a very small protein needed to sequentially sample all possible folding shapes before achieving its proper conformation, and each folding event occurred on the femtosecond timescale, it would take longer than the age of the Universe to achieve proper folding. The full mechanisms for protein folding have remained surprisingly elusive, although it is known that drug molecules called pharmacological chaperones can play a crucial role in facilitating the process. Finding out how proteins are folded into their proper conformation is an important INTELLIGENCE endeavour of biological research since a protein’s conformation determines its function and misfolded proteins can cause widespread cellular damage or even cell death. It is worth noting that it has been estimated that 40 per cent of human diseases involve protein misfolding as part of their pathology. evidence for this mechanism in neurons as well. As she explains: “The biogenesis of both inhibitory and excitatory neurotransmitter receptors appear to be subject to this type of proteostatic regulation. At this point our research has generated many more questions than answers”. THE RIGHT BALANCE COLLABORATIVE EFFORTS Dr Nancy J Leidenheimer is working to better understand the mechanisms that underlie neurotransmitter receptor biogenesis, specifically that of GABAA, an inhibitory receptor important for ionotropic chloride ion conductance. She seeks to provide information critical for elucidating brain function by first understanding the biochemistry of receptors, particularly how their formation is regulated in a cell organelle called the endoplasmic reticulum. The GABAA receptor represents an extremely important therapeutic target due to its central role in maintaining neuronal inhibition. Perturbations of this inhibitory tone in favour of excitation can lead to a wide range of disorders; most notably epilepsy, anxiety and insomnia. Many current treatments for such disorders increase GABAA receptor activity. Leidenheimer’s work relies predominantly on two distinct cell culture model systems. The first is rat brain neuronal cultures which allow GABAA receptor biogenesis to be assessed in a native neuronal environment. In the other model, GABAA receptor DNA is introduced into a non-neuronal cell, resulting in the induced expression of the GABAA receptor: “This reductionist approach allows us to study the receptor by isolating it from the complexities of neurotransmission,” Leidenheimer reveals. For many proteins, folding in the endoplasmic reticulum appears to be an inefficient process with inefficiently folded proteins often destined for degradation without use. Thus, in many cases the properly folded protein only forms a fraction of its total protein present in a cell due to ‘inefficient’ protein folding processes. “This inefficiency has long been a mystery given the general efficiency of biological mechanisms,” Leidenheimer explains. However, it may not actually be the case that folding is wastefully inefficient. This could instead merely reflect an incomplete understanding of proteostatic mechanisms. Leidenheimer’s research supports this latter view, positing that protein folding ‘inefficiency’ serves a useful purpose, performing a regulatory role that allows the amount of properly folded, functionally active protein to be tightly controlled. A major arm of Leidenheimer’s research stems from this view and she is now exploring the possibility that neurotransmitters may enter the endoplasmic reticulum and exert a direct effect on their receptor biogenesis. Thus, she proposes that the neurotransmitter GABA acts as a ‘cognate ligand chaperone’ for its receptor, the GABAA receptor. This is particularly exciting because it provides an additional mechanism by which a neurotransmitter can regulate the amount of active receptor, through the proteostatic control of receptor biogenesis. Leidenheimer has shown that GABA performs the role of chaperone for its receptor in a recombinant expression system and has strong In both systems she employs fluorescent microscopy and a wide range of immunological and biochemistry techniques to determine the localisation of receptors and the interaction of the receptor with other proteins during the ‘quality control’ phase of receptor biogenesis. Through her collaborative efforts with Dr Sheryl Smith of the SUNY Downstate Medical Center, Leidenheimer has used electrophysiological recordings to show that GABAA receptors that are chaperoned by GABA retain their functional capacity at the cell surface. In another collaboration with Dr Charles Meshul of the Oregon Health Sciences University, GABA has been detected in the endoplasmic reticulum of neurons using electron microscopy. WIDER CONTEXT This work is not simply transforming our basic understanding of biogenesis and receptor expression, but will hopefully also have farreaching consequences that translate to the bedside. An understanding of the factors controlling GABAA receptor formation opens the possibility of developing novel drugs for the treatment of a variety of brain disorders, particularly those that centre on GABAA receptor dysfunction or an imbalance between excitation and inhibition in the central nervous system. Pharmacological chaperones also represent a growing field of study, and are viewed with optimism as a potential source of many future clinical breakthroughs in relation to the treatment of protein folding disorders. Leidenheimer hopes pharmacological chaperones will provide some effective alternatives to current GABAA targeting drugs, which are problematic due to the tolerance and addiction that often occur during treatment: “Currently our lab is developing a high throughput, cell based drug screen for the discovery of GABAA receptor pharmacological chaperones”. MECHANISMS OF NEUROTRANSMITTER RECEPTOR BIOGENESIS AND TRAFFICKING OBJECTIVE To unravel the mechanisms that underlie neurotransmitter receptor biogenesis. KEY COLLABORATORS Charles K Meshul, PhD, Research Biologist and Director, Electron Microscopy Facility, Portland Veterans Administration Medical Center and Professor, Department of Behavioral Neuroscience and Pathology, Oregon Health & Science University Sheryl S Smith, PhD, Professor of Physiology and Pharmacology, SUNY Downstate Medical Center FUNDING National Institutes of Health (NIH) grants 2R01MH602640-07; 5R03NS075526-02 CONTACT Dr Nancy J Leidenheimer Professor, Department of Biochemistry and Molecular Biology Louisiana State University Health Sciences Center Shreveport 1501 Kings Highway Shreveport Louisiana, 71130 USA T +1 318 675 7855 E [email protected] NANCY LEIDENHEIMER, PHD is a Professor in the Department of Biochemistry and Molecular Biology and an adjunct professor in the Department of Pharmacology, Toxicology and Neuroscience at Louisiana State University Health Sciences Center in Shreveport. She has served on National Institutes of Health grant review panels and on the Editorial Board of the Journal of Biological Chemistry. She most recently guest-edited a focus issue of the journal Pharmacological Research entitled Pharmacological Chaperones: On the Frontier of 21st Century Therapeutics. Leidenheimer’s work is supported by the National Institutes of Health, specifically the National Institute of Mental Health and National Institute of Neurological Disorders and Stroke. WWW.RESEARCHMEDIA.EU 129