Neuroscience
Online
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Section I:
Cellular and Molecular Neurobiology
13. Amino Acid Neurotransmitters
Part 5 of 5
Neal Waxham, Ph.D.
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Termination of Action
Two basic mechanisms, diffusion and high
affinity uptake, terminate the response to amino acid transmitters. The high
affinity uptake mechanism is the most predominant. The proteins involved in transmitter
uptake are related and each contains 12 membrane-spanning domains. Transporters
use energy derived either from the hydrolysis of ATP or electrochemical ion gradients
established across the membrane to pump the transmitters into neurons and glia.
The energy-dependent nature of these receptors means that in times of metabolic
stress, such as during an ischemic episode, the pumps fail and toxic levels of
these transmitters build up.
Clinical Manifestations of Altered Glutamate Levels
The neurotransmitter glutamate is highly toxic to neurons when present for extended
periods. One of the best understood clinical conditions involving glutamate is
neuronal injury following stroke or trauma.
Both events produce massive release of glutamate in the brain that over-stimulates
glutamate receptors. The absence of energy prevents the pumps from removing glutamate
from the synapse. As a consequence, the uncontrolled opening of glutamate receptors
causes a large influx of Na+ followed by water that produces swelling
and a large and sustained influx of Ca2+ that leads to hyperactivation
of many calcium-dependent enzymes. The Ca2+ influx through the NMDA
receptor appears to be one of the keys to producing neuronal damage since specifically
blocking activation of this receptor attenuates some of the neuronal injury following
stroke. The key to minimizing damage following stroke is well-controlled reestablishment
of blood flow so that ATP production is supported and homeostasis is reestablished.
Clot breaking agents such as tissue plasminogen activator
(tPA) are now used commonly to reestablish blood flow.
Because glutamate is the major excitatory transmitter in the human brain, derangements
in glutamate metabolism or receptor activation have been implicated in a wide
variety of pathologic conditions. These include diseases such as Alzheimer's
and Huntington's chorea.
Diseases Associated with GABA
One explanation for the establishment of focal epilepsy
is decreased local GABA-mediated inhibition. Many facets of epilepsy can be elicited
experimentally by blocking GABA receptors with the toxin picrotoxin
previously described. The decrease in GABA inhibition permits cells to fire synchronously,
thus producing massive local excitation and initiation of a seizure. Clinically,
seizures can often be terminated by inducing a barbiturate coma. High dose barbiturates
presumably potentiate GABA's inhibitory effects, preventing local hyperexcitation
by hyperpolarizing the cell membranes.
Mood disorders (generalized anxiety disorder) can also
be controlled by drugs which potentiate GABA's inhibitory activity. Some of
the most widely prescribed drugs-benzodiazepines (Librium and Valium)-produce
their pharmacological effects by increasing GABA's ability to hyperpolarize
neuronal membranes, thereby quieting the system. This finding suggests that
some initial imbalance in the GABAergic system may underlie aspects of this
disorder.
Contact the author(s) at: nba_course@uth.tmc.edu
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The University of Texas Health Science Center at Houston
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