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GABAA Receptor: Knocked Out
Whitefish Bay SMART Team: Jack Middleton, Wentong Zhang, Shawn Wang, Na’il Scoggins, Frank Zhang, John Park, John Schroeder,
Sam Broadnax, Jieun Heo and Morgan Phillips
Teachers: Paula Krukar, Marisa Roberts, Lisa Krueger and Katie Brown
Mentor: Robert Peoples, Ph.D., Department of Biomedical Sciences, Marquette University
Abstract
Synaptic Cleft
Location of Propofol-Binding
Today, surgeons and dentists would not consider operating without the use of
anesthetics, drugs that help numb pain and induce unconsciousness by inhibiting
the transmission of signals in nerve cells. The GABAA receptor is a transmembrane
receptor protein activated by the neurotransmitter gamma-aminobutyric acid
(GABA) that plays a crucial role in the action of proprofol as an anesthetic. The
Whitefish Bay SMART (Students Modeling A Research Topic) Team is modeling the
GABAA receptor protein using 3D printing technology. When activated, the GABAA
receptor selectively allows chloride ions to pass through the membrane and into
the cell, creating a more negative overall charge inside the cell. When a nerve cell is
excited, a sudden change in ion concentrations triggers an electrochemical
potential across the cell membrane, ultimately resulting in the passage of the
original signal to the next neuron. However, the GABAA receptor acts as an
inhibitor, and impedes the spreading of the message by making the cell less likely to
be in an excited state, causing the cell to relay a neural signal less frequently.
Propofol produces its effects by enhancing the activity of the GABAA receptor.
Currently, researchers are trying to pinpoint how propofol acts on the GABAA
receptor protein because its molecular mechanism is not fully understood. It has
been found that a phenylalanine at position 385 on the GABAA receptor is
necessary for propofol to produce its effects. Research targeting how propofol
alters the function of the GABAA receptor may lead to the development of more
effective anesthetics with fewer side effects.
The space between two neurons is the synaptic cleft. The GABAA receptor is a transmembrane
receptor protein activated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).
Under normal conditions, GABA is released from one neuron and is received by the GABAA receptor
protein found in the membrane of the other neuron, inhibiting its activity. In the presence of propofol
the GABAA receptor is more easily activated by GABA, resulting in the termination of the signal.
In order to determine the location of propofol binding, researchers
conducted mutational analysis. The figure below illustrates the
importance of the amino acids from 354 to 388 in presence of
propofol. It is evident that deletion of these amino acids results in
a lower potentiation of current by the GABAA receptors. Because of
this, the GABAA receptor protein is less responsive to propofol,
resulting in a more responsive neuron and thus reducing the effects
of propofol as an anesthetic.
The Nervous System
Normal
With Propofol
A
In the potentiation curves (B in the figure below), the chloride ion
current is measured under different conditions. In the wild type,
the addition of propofol increased the chloride ion current.
However, when amino acids 354-388 are deleted, the current is
only slightly changed, indicating the significance of these amino
acids.
A
Neuron A
fires,
sending an
excitatory
signal
Neuron A
fires,
sending an
excitatory
signal
B
B
indianapublicmedia.org
GABA
The brain is the command center of the human body. Signals from
all over the body are ultimately received in the brain. Anesthetics
drastically reduce signaling in the brain. This results in a loss of
responsiveness and unconsciousness. Thus, anesthetics are
administered prior to surgery to induce a state of
unconsciousness. The drugs increase inhibition in the brain,
resulting in the non-transfer of excitatory electrochemical signals.
Therefore, the patient is rendered unconscious and pain is not felt,
which allows major surgery to be performed.
GABA
GABA-releasing
neuron
GABA-releasing
neuron
C
C
If the GABAA receptor is mutated, the protein is less responsive to
propofol, resulting in a more responsive neuron and thus mitigating
the effects of propofol as an anesthetic.
GABAA receptor
Significance of Propofol
Propofol is one of the most commonly used
anesthetics in modern medicine. Propofol
interacts with the GABAA receptor protein
resulting in the termination of a signal.
When enough signals are inhibited, brain
Structure of Propofol
function slows to the point that the body
enters a state of unresponsiveness, leading to unconsciousness.
Too much inhibition causes the nervous system to shut down,
resulting in coma or even death. Each year in the United States,
misuse of anesthetics results in 34 deaths and is a contributing
factor for another 281. By understanding the interaction between
GABAA protein receptors and propofol, researchers can synthesize
new compounds to serve as better anesthetics in hopes of
reducing the number of complications of anesthetics.
Signal is
propagated
Propofol
GABAA receptor
Signal is
stopped
When the GABAA receptor is activated, it
allows negatively charged chloride ions to pass
through its channel, making the membrane
voltage more negative and the neuron less
likely to fire. This inhibition may block the
transmission of the signal from the nerve cell.
However, the signals may still pass and the cell
may still transfer the message.
Propofol is an allosteric modulator, which
means that it effectively enhances the effects
of the GABAA receptor protein without binding
to the GABA site. The chloride ions flow into
the neuron, making the membrane voltage
highly negative, which results in the
termination of the original signal.
Conclusion
While significant advances have been made in understanding the
function of the GABAA receptor protein, there is still more to learn
about the active sites of the protein. Currently, scientists
understand the general function of propofol - the anesthetic
enhances the GABAA’s function of inhibiting neural signals from
traveling, which in turn results in normal human alertness to be
replaced with sedation or loss of consciousness. However, it is
unclear exactly how propofol affects the GABAA receptor, and
research may be able to aid in uncovering this mystery. Potential
benefits of this research would be that anesthetics would be safer
and more effective. Although the understanding of the effect of
propofol has come a long way, more milestones must be reached in
order to ensure a safer and more effective use of this and other
anesthetics.
Works Cited
Moraga-Cid, Gustavo, Gonzalo, E., Yevenes, Gunther, Schmalzing, Robert, W., Peoples, Luis, G., Aguayo. "A Single Phenylalanine
Residue in the Main Intracellular Loop of α1 γ-aminobutyric Acid Type A and Glycine Receptors Influences Their Sensitivity
to Propofol." (2011)
Fischer, Andreas. "Under the Knife: Study Shows Rising Death Rates from General Anesthesia." Time. Time, 4 Aug. 2011. Web.
25 Feb. 2013.
The SMART Team Program (Students Modeling A Research Topic) is funded by a grant from NIH-SEPA 1R25OD010505-01 from NIH-CTSA UL1RR031973.