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GABAA Receptor’s Role in Keeping the Brain Calm Pius XI SMART Team: Steven Brzezinski, James Carian, Katie Eszes, Bilal Garner, Brittany Givens, Jenna Motz, Bernie Mulvey, Richa Rathore,Joseph Schwemmer, Kathryn Sulik, Stefan Thompson, Jordan Zawacki, Sydney Zettler Teachers: Julie Fangmann, Mimi Verhoeven Mentor: David Wagner, PhD, Marquette University Abstract Numerous neurological pathologies, such as anxiety disorders, epilepsy, and insomnia, are due to neurons in the brain malfunctioning by being overactive. Like a stop sign directing traffic, the activation of gamma-amino butyric acid (GABAA) receptors reduces neural activity preventing neurons from firing excessively. When GABA binds to the GABAA receptor, negative chloride ions flow into the neuron. This inhibits neural activity because neurons need a net positive charge inside them to send messages. GABAA receptors are targets for depressants, including alcohol, benzodiazepines (such as Ambien™, Valium™, and Xanax™), and general anesthetics. These drugs bind to the GABAA receptor to increase inhibition of neural activity. The specific GABA binding site(s) on the GABAA receptor are unknown. Current research focuses on altering amino acids potentially involved in binding GABA. If one of these amino acids in the binding site is altered, GABA will unbind faster from this mutated GABAA receptor than it does from the wild type (normal) receptor. Finding the specific amino acids involved in binding GABA could lead to breakthroughs in GABAA receptor-related pathologies and allow for better design of new drugs. I. Basic Function of Neurons Introduction Epilepsy results from neurons firing out of control when GABAA receptors do not inhibit them properly. AmbienTM allows people to sleep by targeting GABAA receptors and making them more effective. II. GABA and the GABAA Receptor α GABA γ α α-ß Interfaces GABA Receptor Top View GABA (an inhibitory neurotransmitter) is released by neurons in the brain into synapses, where it binds to the α-ß interface of the five-subunit GABAA receptors on other neurons. This binding inhibits neural signals from being transmitted. IV. Proposed GABA Binding Sites The exact location of the binding site of GABA is unknown. Current research focuses on several amino acids (such as ßArg207, ßPhe200, αArg120, and αArg67) in the α-β interfaces of GABAA receptors. Dr. David A. Wagner mutates amino acids on the GABAA receptor to determine how it alters the rate at which GABA unbinds, thus indicating if it plays a role in GABA binding. α β Cell Membrane No GABA: closed receptor Neuron can send messages βPhe200 GABA α-β Interface of GABA Receptor PDB file: O’Mara et al 2005 GABA-A.pdb PDB file ID: 2OKK Poster Image Sources: http://www.sciencemag.org/sciext/vis2005/show/images/slide1_large.jpg, http://www.txtwriter.com/backgrounders/drugaddiction/synapse.jpg http://www.humanillnesses.com/original/images/hdc_0001_0001_0_img0080.jpg, http://www.infantile-spasms.org/images/child%20eeg.jpg http://images-cdn01.associatedcontent.com/image/A7567/75670/300_75670.jpg Synapse GABA binds: open receptor Neuron signaling is inhibited The GABAA receptor is a chloride ion channel. When activated, the channel opens and negative chloride ions pass into the neuron. The accumulation of these negative ions inhibits neural firing. If GABA does not bind long enough, neurons fire out of control, causing insomnia or even seizures. GABA unbinds much faster from R207A mutant GABAA receptors compared to the wild type GABAA receptors αArg67 GABA Receptor Side View β Cl- αArg120 βArg207 α Inside of Neuron PDB file: O’Mara et al 2005 GABA-A.pdb Neurons (nerve cells) meet at synapses (gaps) where neurotransmitters (chemical messages) are passed from one neuron to receptors on another neuron. III. Neural Inhibition Due to GABA Binding β β Seizures and insomnia are more common than most people realize. These pathologies occur when brain cell activity is not properly regulated. GABA, a chemical, slows brain cell activity when it binds to its receptor. If the GABAA receptor is misshapen, GABA cannot bind, making it less effective at inhibiting neural activity. If brain cells fire uncontrollably, then insomnia or seizures may occur. Drugs, such as alcohol, benzodiazepines (Ambien ™) and general anesthetics, currently target GABAA receptors, but the exact GABA binding site is currently unknown. A mutation in one amino acid (Arg207) causes GABA to unbind much more quickly than GABA unbinds from the wild type (unmutated) GABAA receptor. In this case (βR207A), the 207th amino acid (an arginine) is mutated to alanine. These data suggest this particular amino acid is part of the GABA binding site. Future Research and Drug Design The exact GABA binding site on the GABAA receptor remains a mystery. As research continues to improve knowledge of the GABAA receptor, new drugs can be designed to specifically target the GABAA receptor’s GABA binding site. These drugs could then inhibit neural firing more effectively, offering better treatment of insomnia and epilepsy.