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Over the Limit, Under Arrest
The NMDA Receptor and the Effect of Alcohol
Cudahy SMART Team: Rebecca Fansler, Sara Kutcher, Amber Perkins, Liz Michalzik, Roxanne Thiede, Laura Harrold,
Paige Broeckel, Amber Haapakoski, Virginia Lachenschmidt, Jasmin Jones
Teacher: Dan Koslakiewicz
Cudahy High School 4950 S Lake Dr Cudahy, WI 53110
The Process of Synaptic Transmission
Abstract
Alcohol, or ethanol, is one of the most abused drugs
worldwide, dating back to ancient cultures including
Mesopotamia. Effects of alcohol on behavior are wellknown, such as incoherence and lack of coordination.
Overconsumption of ethanol can lead to alcoholism,
which is related to genetic variations and brain chemistry.
In the brain, proteins such as the N-methyl-D-aspartate
(NMDA) receptor are responsible for multiple cognitive
functions. The NMDA receptor binds glutamate, a major
neurotransmitter, transferring signals from one neuron to
another across the synapse, or gap between neurons.
When ethanol is not present in the system, glutamate
binds to the NMDA receptor on the post-synaptic cell and
opens the ion channel, allowing sodium and calcium to
enter and excite the cell. Ethanol, when present, crosses
the protective blood-brain barrier and appears to bind to
specific amino acid side chains: Ala825, Phe637, Met823,
Val820, Phe639, and Leu824, which are in the
transmembrane portion of the NMDA receptor GluN1 and
GluN2A subunits. Ethanol limits NMDA receptor function
by inhibiting the ion channel gate from opening and
depolarizing the membrane. When ethanol binds to sites
in the transmembrane domain, the conformational change
of the NMDA receptor is inhibited, blocking the flow of
sodium and calcium into the neuron, preventing synaptic
transmission. By learning how ethanol interacts with the
NMDA receptor to change its function, researchers hope
to discover better treatments for alcoholism. The Cudahy
SMART Team (Students Modeling A Research Topic)
modeled the NMDA receptor, highlighting important
structures, using 3D printing technology.
Mentor: Robert Peoples, PhD.
Marquette University
Nerves communicate by sending chemical signals, called neurotransmitters, across the space between cells, called a synapse. To accomplish this, a neurotransmitter is
released from a vesicle in a presynaptic neuron, the neuron initiating the signal process. The neurotransmitters are released into the synapse and bind to receptor proteins on
the postsynaptic neuron, continuing transmission of the signal, called an action potential. When an excitatory neurotransmitter binds to a receptor protein, such as the N-methylD-aspartate, NMDA, receptor, it causes a conformational change to the protein, allowing sodium to enter the postsynaptic neuron from the intercellular space. When sodium
enters the postsynaptic cell, the cell voltage becomes more positive, depolarizing it to reach threshold. This is the necessary voltage for an action potential to occur in the
postsynaptic neuron. If the neurotransmitter is inhibitory, it will oppose depolarization to threshold.
Synaptic Transmission
NMDA Receptor Under Normal Conditions
NMDA Receptor When Ethanol is Present
Neuronal signaling requires the release of a
neurotransmitter into the synaptic cleft. In the
absence of alcohol, an excitatory neurotransmitter,
glutamate, is released by the presynaptic neuron.
Upon binding to the NMDA receptor on the
postsynaptic neuron, which is a sodium channel,
glutamate stimulates the influx of sodium ions
through the channel and into the postsynaptic
neuron, depolarizing it. As shown in the figure
below, if this excitatory postsynaptic potential
(EPSP; a voltage change) reaches threshold, the
minimum voltage change needed to stimulate an
action potential, the neuronal signal continues
through the system.
When ethanol, or alcohol, is present in the
synapse, it can attenuate the propagation of the
neuronal
signal.
Ethanol
binds
to
the
transmembrane portion of the NMDA receptor at
specific amino acid residues at four potential
binding sites in the M3 and M4 domains. These
interactions are likely the result of hydrophobic
interactions between ethanol and the receptor.
When bound to the receptor, ethanol prevents the
ion channel from fully opening. As shown in the
figure below, the EPSP does not reach the
threshold needed to induce an action potential.
When this happens in the brain, functions such as
judgment, coordination, and planning are
impaired.
Transmembrane Portion of
NMDA Receptor
Roberts, A. (2010). The complete human body: the
definitive visual guide.. New York: DK Publishing.
Ethanol
PBD File: EOH
PBD File: 3KG2
Data Supports the Role of Specific Amino Acid Residues in the NMDA Receptor as the Sites Influenced by Alcohol
Ethanol reduces the Na+-produced current across the NMDA
• Amino acids in key positions were mutated and current across the receptor was
measured and compared to wild-type in response to the addition of glutamate
alone, and glutamate in the presence of ethanol.
• Sodium-produced currents are shown in the graphs to the left. An elevated line
indicates inhibition.
• Data reveal that when mutated in key positions, ethanol did not inhibit the sodium
current as effectively as in the wild-type, thus indicating the importance of these
amino acids in binding ethanol.
Higher concentrations of ethanol required in mutations to elicit inhibition
• Different mutations required different concentrations of ethanol for inhibition, with
the F636 mutant being the least sensitive to the effects of ethanol.
• Data show Ala825, Phe637, Met823, Val820, Phe639, and Leu824 are the key
residues to bind ethanol.
Citations
Ren, H., Salous, A., Lipsky, R., & Peoples, R. (2007). Mutations at F637 in the NMDA receptor NR2A subunit M3 domain influence agonist potency, ion channel gating and alcohol action. British Journal of Pharmacology, 151, 749-757.
Ren, H., Salous, A., Paul, J., Lamb, K., Dwyer, D., & Peoples, R. (2008). Functional interactions of alcohol-sensitive sites in the N-methyl-D-aspartate receptor M3 and M4 domains. The Journal Of Biological Chemistry, 283(13), 8250-8257.
A SMART Team project supported by the National Institutes of Health Science Education Partnership Award (NIH-SEPA 1R25RR022749) and an NIH CTSA Award (UL1RR031973).
Ethanol Sensitivity and Brain Function
Alcohol primarily affects the frontal lobes of the brain.
When alcohol, or ethanol, blocks the N-methyl-D-aspartate
receptor the person experiences loss of motor coordination
and inhibitions. Alterations in sensitivity of brain target
proteins may be why alcoholics drink more. They may be
less sensitive to ethanol, so it takes more ethanol to
achieve the same effect as someone who is more
sensitive.
Frontal
Lobes
http://www.idsia.ch/NNcourse/brain.html
Conclusions
The effects of alcohol on the human body are outwardly visible. Many areas in the
brain are affected by alcohol, including inhibition of judgment or reason. This is partly
achieved through the block of the NMDA receptor by ethanol. Through research on
the NMDA receptor, one can see the effects of ethanol at the molecular level and
perhaps a potential link to alcohol sensitivity can be determined through an
understanding of which amino acids interact directly with ethanol. From these studies
an effective treatment of alcohol abuse and alcoholism may be discovered.
Ren, H., Honse, Y., & Peoples, R. (2003). A site of alcohol action in the fourth membrane-associated domain of the N-methyl-D-aspartate receptor. The Journal Of Biological
Chemistry, 278(49), 48815-48820.
Sobolevsky, A., Rosconi, M., & Gouaux, E. (2009). X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature, 462, 745-756.