gaba a receptor: knocked outcbm.msoe.edu/images/contentimages/smartteams/alumni... · location of...

Location of Propofol-Binding 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.

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.

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.

Synaptic CleftThe 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.

GABAA Receptor: Knocked OutWhitefish 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

The SMART Team Program (Students Modeling A Research Topic) is funded by a grant from NIH-SEPA 1R25OD010505-01 from NIH-CTSA UL1RR031973.

The Nervous System

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.

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

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.

AbstractToday, 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.

Normal With Propofol

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.

ConclusionWhile 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.

Structure of Propofol

Signal is

propagated

Neuron A

fires,

sending an

excitatory

signal

A

B

C

GABAA receptor

GABA

GABA-releasing

neuron

Neuron A

fires,

sending an

excitatory

signal

A

B

C

GABAA receptor

GABA

GABA-releasing

neuron

Signal is

stopped

Propofol

indianapublicmedia.org