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.
