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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.