ININFA   02677
INSTITUTO DE INVESTIGACIONES FARMACOLOGICAS
Unidad Ejecutora - UE
capítulos de libros
Título:
Pharmacology of the GABA-A receptor
Autor/es:
DMYTRO BEREZHNOV; MARIA CLARA GRAVIELLE; DAVID FARB,
Libro:
The Handbook of Contemporary Neuropharmacology
Editorial:
J. Wiley and Sons, Inc
Referencias:
Lugar: New York; Año: 2007; p. 1 - 1
Resumen:
Although the human central nervous system (CNS) is undoubtedly a marvel of
implementation of cellular systems, composed of roughly 1013 neurons each making
thousands of synaptic connections, their functional output can be expressed in terms
of a balance between excitatory and inhibitory synaptic activity. Approximately onethird
of brain synapses use g-aminobutyric acid (GABA) as the inhibitory neurotransmitter
[13]. Experiments carried out during the 1950s and 1960s suggested that
GABA has an inhibitory effect in the invertebrate [46] and the vertebrate CNS [715].
The molecular diversity of type A GABA (GABAA) receptor subunit genes probably
evolved by a process of duplication and translocation of an ancestral gene, leading to
modern-day gene clusters distributed on different human chromosomes [1618].13 neurons each making
thousands of synaptic connections, their functional output can be expressed in terms
of a balance between excitatory and inhibitory synaptic activity. Approximately onethird
of brain synapses use g-aminobutyric acid (GABA) as the inhibitory neurotransmitter
[13]. Experiments carried out during the 1950s and 1960s suggested that
GABA has an inhibitory effect in the invertebrate [46] and the vertebrate CNS [715].
The molecular diversity of type A GABA (GABAA) receptor subunit genes probably
evolved by a process of duplication and translocation of an ancestral gene, leading to
modern-day gene clusters distributed on different human chromosomes [1618].g-aminobutyric acid (GABA) as the inhibitory neurotransmitter
[13]. Experiments carried out during the 1950s and 1960s suggested that
GABA has an inhibitory effect in the invertebrate [46] and the vertebrate CNS [715].
The molecular diversity of type A GABA (GABAA) receptor subunit genes probably
evolved by a process of duplication and translocation of an ancestral gene, leading to
modern-day gene clusters distributed on different human chromosomes [1618].A) receptor subunit genes probably
evolved by a process of duplication and translocation of an ancestral gene, leading to
modern-day gene clusters distributed on different human chromosomes [1618].
L-Glutamic acid decarboxylase (GAD) catalyzes the conversion of L-glutamate to
GABA via a decarboxylation resulting in the accumulation and storage of GABA
within inhibitory neurons [5, 19, 20]. Upon arrival of an action potential at the nerve
terminal, the presynaptic membrane depolarizes inducing the opening of voltagegated
Ca2þ channels. In.ux of Ca2þ ions through these channels increases its
intracellular concentration and triggers the fusion of synaptic vesicles containing
GABA with the presynaptic membrane. When released into the synaptic cleft GABA
freely diffuses within the 20-nm synaptic cleft and binds to both post- and presynaptic
receptors. Termination of synaptic transmission is achieved by clearing the neurotransmitter
by a combination of diffusion out of the cleft and active transport into
contiguous neuronal and/or glial cells [21].
Once recaptured by the neuron, GABA can be further transported into synaptic
vesicles by vesicular GABA transporters (VGATs) or degraded by the enzyme
GABA aminotransferase to succinic semialdehyde [22]. Different plasma membrane
transporters are responsible for high-af.nity uptake of GABA into neuronal cells.
These membrane-bound transport proteins are dependent on the Naþ transmembrane
gradient and may require either Cl or Kþ for activity [2325].
The accumulation of intraneuronal GABA into storage vesicles theoretically
increases the potential concentration gradient across the plasma membrane by
compartmentalization of releasable GABA, protecting it from leakage and/or
intraneuronal metabolism.-Glutamic acid decarboxylase (GAD) catalyzes the conversion of L-glutamate to
GABA via a decarboxylation resulting in the accumulation and storage of GABA
within inhibitory neurons [5, 19, 20]. Upon arrival of an action potential at the nerve
terminal, the presynaptic membrane depolarizes inducing the opening of voltagegated
Ca2þ channels. In.ux of Ca2þ ions through these channels increases its
intracellular concentration and triggers the fusion of synaptic vesicles containing
GABA with the presynaptic membrane. When released into the synaptic cleft GABA
freely diffuses within the 20-nm synaptic cleft and binds to both post- and presynaptic
receptors. Termination of synaptic transmission is achieved by clearing the neurotransmitter
by a combination of diffusion out of the cleft and active transport into
contiguous neuronal and/or glial cells [21].
Once recaptured by the neuron, GABA can be further transported into synaptic
vesicles by vesicular GABA transporters (VGATs) or degraded by the enzyme
GABA aminotransferase to succinic semialdehyde [22]. Different plasma membrane
transporters are responsible for high-af.nity uptake of GABA into neuronal cells.
These membrane-bound transport proteins are dependent on the Naþ transmembrane
gradient and may require either Cl or Kþ for activity [2325].
The accumulation of intraneuronal GABA into storage vesicles theoretically
increases the potential concentration gradient across the plasma membrane by
compartmentalization of releasable GABA, protecting it from leakage and/or
intraneuronal metabolism.a decarboxylation resulting in the accumulation and storage of GABA
within inhibitory neurons [5, 19, 20]. Upon arrival of an action potential at the nerve
terminal, the presynaptic membrane depolarizes inducing the opening of voltagegated
Ca2þ channels. In.ux of Ca2þ ions through these channels increases its
intracellular concentration and triggers the fusion of synaptic vesicles containing
GABA with the presynaptic membrane. When released into the synaptic cleft GABA
freely diffuses within the 20-nm synaptic cleft and binds to both post- and presynaptic
receptors. Termination of synaptic transmission is achieved by clearing the neurotransmitter
by a combination of diffusion out of the cleft and active transport into
contiguous neuronal and/or glial cells [21].
Once recaptured by the neuron, GABA can be further transported into synaptic
vesicles by vesicular GABA transporters (VGATs) or degraded by the enzyme
GABA aminotransferase to succinic semialdehyde [22]. Different plasma membrane
transporters are responsible for high-af.nity uptake of GABA into neuronal cells.
These membrane-bound transport proteins are dependent on the Naþ transmembrane
gradient and may require either Cl or Kþ for activity [2325].
The accumulation of intraneuronal GABA into storage vesicles theoretically
increases the potential concentration gradient across the plasma membrane by
compartmentalization of releasable GABA, protecting it from leakage and/or
intraneuronal metabolism.2þ channels. In.ux of Ca2þ ions through these channels increases its
intracellular concentration and triggers the fusion of synaptic vesicles containing
GABA with the presynaptic membrane. When released into the synaptic cleft GABA
freely diffuses within the 20-nm synaptic cleft and binds to both post- and presynaptic
receptors. Termination of synaptic transmission is achieved by clearing the neurotransmitter
by a combination of diffusion out of the cleft and active transport into
contiguous neuronal and/or glial cells [21].
Once recaptured by the neuron, GABA can be further transported into synaptic
vesicles by vesicular GABA transporters (VGATs) or degraded by the enzyme
GABA aminotransferase to succinic semialdehyde [22]. Different plasma membrane
transporters are responsible for high-af.nity uptake of GABA into neuronal cells.
These membrane-bound transport proteins are dependent on the Naþ transmembrane
gradient and may require either Cl or Kþ for activity [2325].
The accumulation of intraneuronal GABA into storage vesicles theoretically
increases the potential concentration gradient across the plasma membrane by
compartmentalization of releasable GABA, protecting it from leakage and/or
intraneuronal metabolism.þ transmembrane
gradient and may require either Cl or Kþ for activity [2325].
The accumulation of intraneuronal GABA into storage vesicles theoretically
increases the potential concentration gradient across the plasma membrane by
compartmentalization of releasable GABA, protecting it from leakage and/or
intraneuronal metabolism. or Kþ for activity [2325].
The accumulation of intraneuronal GABA into storage vesicles theoretically
increases the potential concentration gradient across the plasma membrane by
compartmentalization of releasable GABA, protecting it from leakage and/or
intraneuronal metabolism.