GABA transporter

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GABA transporters (gamma-aminobutyric acid transporters) are a family of neurotransmitter / sodium symporters, belonging to the solute carrier 6 (SLC6) family. [1] [2] . They are found in various regions of the brain in different cell types, such as neurons and astrocytes.

Contents

These transporters are primarily responsible for the regulation of extracellular GABA concentration during basal and synaptic activity. They are responsible for creating a GABA gradient which is determined by the membrane potential, and the concentration of Na+ and Cl. They are also present on the plasma membrane of neurons and glia which help define their function of regulation of GABA concentration as they act as the receptors that facilitate recycling of GABA in the extracellular space. [1] GABA transporters are a common target for anticonvulsant drugs against seizure disorders such as epilepsy. [3]

Types

Molecular phylogenetic analysis of the SLC6 neurotransmitter transporter family in Homo sapiens Fncel-08-00161-g0001.jpg
Molecular phylogenetic analysis of the SLC6 neurotransmitter transporter family in Homo sapiens

The GABA transporter group consists of six different transporters:

GAT1 and GAT3 are the major GABA transporters in the brain and spinal cord, expressed by both neurons and some astrocytes. [4] GAT2 and BGT1 are also expressed in the brain, but at low levels and mostly in the meninges. GAT2 also transports taurine, while BGT1 transports betaine. These two transporters are predominantly expressed in the liver, but are also found in the kidneys and, as mentioned above, in the meninges. [4]

Function

The cartoon depicts a GABAergic synapse in adult rat brain where GABA is released exocytotically and acts upon specific post-synaptic receptors. The signal is terminated by removal of GABA from the synaptic cleft by transport of GABA back into the nerve terminal by the plasma membrane GABA transporter (GAT) 1. Fendo-08-00190-g001.jpg
The cartoon depicts a GABAergic synapse in adult rat brain where GABA is released exocytotically and acts upon specific post-synaptic receptors. The signal is terminated by removal of GABA from the synaptic cleft by transport of GABA back into the nerve terminal by the plasma membrane GABA transporter (GAT) 1.

GABA transporters in the plasma membrane help in regulating the concentration of GABA in the extracellular matrix by reabsorbing the transmitter and clearing the synapse. They transiently bind to GABA in the extracellular matrix and translocate the transmitter in the cytoplasm. The GABA transmitters are not broken down but are cleared via GABA transporters through re-absorption from the synaptic cleft. [1] There is only a 20% loss of the transmitters during each re-absorption while nearly 80% is recycled. [2] The plasma membrane GABA transporters maintain an extracellular GABA concentration in the vicinity of the synapse to control the activity of the GABA receptors. The GABAergic synaptic transmission controls the generation of membrane potential rhythmic changes as the transporters are dependent on Na+ and Cl ions moving in and out of the across the membrane which are determinants of membrane potential. These changes rely on the precise timing of GABA receptors activation which in turn are dependent upon the release and clearance of GABA in the extracellular space. This reuptake of neurotransmitters plays a significant role in the overall process of synaptic transmission. The GABA transporter is an active system, electrogenic, a voltage-dependent which relies on the inward electrochemical gradient of Na+ ions instead of ATP. [5] It also has low micromolecular affinity to GABA with a Michaelis-Menten constant of 2.5 μM, [1] and requires the presence of Cl- ions in the extracellular matrix. The GABA transporter help creates an equilibrium of GABA and will work in the reverse direction if needed to maintain the baseline concentration of GABA in the system. [1]

Structure

The structure of Sl6 family transporters share 20-25% sequence similarity with LeuTA [6] providing an evolutionary relationship between the transporter and the leucine transporter protein. [2] Because of the similarity, the LeuTa protein provides a very close template model for the studying the transporters in greater detail. [1] The GABA transporter exists in two different conformations. The transporters have general structure of 12 alpha helices with both end - N Terminus and C-terminus in the cytoplasm with glycosylation sequence in the transmembrane helices. [7] They also exhibit ligand gated ion channel properties as well as substrate dependent properties of leak current. The amino acid sequence ranges from 599 (GAT1) to 700 for glycine transporters. [5]

Role in epilepsy

Secondary structure and surface representation of LeuTAa. Topology of Aquifex aeolicus LeuTAa. The transporter is composed of 12 trans-membrane regions with cytoplasmic N- and C-terminal domains. TM1 and TM6 are oriented antiparallel to one another and have breaks in their helical structure approximately halfway across the membrane bilayer. The transporter has two extracellular b-strands (green arrows), four extracellular and two intracellular helices PMC4060055 fncel-08-00161-g0002.png
Secondary structure and surface representation of LeuTAa. Topology of Aquifex aeolicus LeuTAa. The transporter is composed of 12 trans-membrane regions with cytoplasmic N- and C-terminal domains. TM1 and TM6 are oriented antiparallel to one another and have breaks in their helical structure approximately halfway across the membrane bilayer. The transporter has two extracellular β-strands (green arrows), four extracellular and two intracellular helices

GABA creates an inhibitory tone in the cerebral cortex to counterbalance the neuronal excitability. [3] An imbalance between the excitability and inhibition often lead to seizures. To help with epilepsy disorder, anticonvulsant drugs are designed which specifically attack the GABA system. These drugs often attack the transporters blocking their activity, which affects the neuronal excitability.  Anticonvulsants such as Tiagabine attack the GABA transporters inhibiting the uptake of GABA neurotransmitter. In patients with temporal lobe seizures, there is a decrease in GABA release because of the impairment of transporters. Drugs such as Vigabatrin cause reversals in GABA transporters that increase the concentration of GABA in the synapse which helps in inhibiting the neuronal excitability. [3]

Related Research Articles

<span class="mw-page-title-main">Neurotransmitter</span> Chemical substance that enables neurotransmission

A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell.

<span class="mw-page-title-main">Chemical synapse</span> Biological junctions through which neurons signals can be sent

Chemical synapses are biological junctions through which neurons' signals can be sent to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.

<span class="mw-page-title-main">Reuptake</span> Reabsorption of a neurotransmitter by a neurotransmitter transporter

Reuptake is the reabsorption of a neurotransmitter by a neurotransmitter transporter located along the plasma membrane of an axon terminal or glial cell after it has performed its function of transmitting a neural impulse.

An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential. The opposite of an inhibitory postsynaptic potential is an excitatory postsynaptic potential (EPSP), which is a synaptic potential that makes a postsynaptic neuron more likely to generate an action potential. IPSPs can take place at all chemical synapses, which use the secretion of neurotransmitters to create cell-to-cell signalling. EPSPs and IPSPs compete with each other at numerous synapses of a neuron. This determines whether an action potential occurring at the presynaptic terminal produces an action potential at the postsynaptic membrane. Some common neurotransmitters involved in IPSPs are GABA and glycine.

<span class="mw-page-title-main">Excitatory postsynaptic potential</span> Process causing temporary increase in postsynaptic potential

In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the flow of positively charged ions into the postsynaptic cell, is a result of opening ligand-gated ion channels. These are the opposite of inhibitory postsynaptic potentials (IPSPs), which usually result from the flow of negative ions into the cell or positive ions out of the cell. EPSPs can also result from a decrease in outgoing positive charges, while IPSPs are sometimes caused by an increase in positive charge outflow. The flow of ions that causes an EPSP is an excitatory postsynaptic current (EPSC).

<span class="mw-page-title-main">Excitatory synapse</span> Sort of synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

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<span class="mw-page-title-main">Glutamate receptor</span> Cell-surface proteins that bind glutamate and trigger changes which influence the behavior of cells

Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

<span class="mw-page-title-main">Neurotransmission</span> Impulse transmission between neurons

Neurotransmission is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron, and bind to and react with the receptors on the dendrites of another neuron a short distance away. A similar process occurs in retrograde neurotransmission, where the dendrites of the postsynaptic neuron release retrograde neurotransmitters that signal through receptors that are located on the axon terminal of the presynaptic neuron, mainly at GABAergic and glutamatergic synapses.

Glutamate transporters are a family of neurotransmitter transporter proteins that move glutamate – the principal excitatory neurotransmitter – across a membrane. The family of glutamate transporters is composed of two primary subclasses: the excitatory amino acid transporter (EAAT) family and vesicular glutamate transporter (VGLUT) family. In the brain, EAATs remove glutamate from the synaptic cleft and extrasynaptic sites via glutamate reuptake into glial cells and neurons, while VGLUTs move glutamate from the cell cytoplasm into synaptic vesicles. Glutamate transporters also transport aspartate and are present in virtually all peripheral tissues, including the heart, liver, testes, and bone. They exhibit stereoselectivity for L-glutamate but transport both L-aspartate and D-aspartate.

<span class="mw-page-title-main">Synapse</span> Structure connecting neurons in the nervous system

In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another neuron or to the target effector cell.

Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons. Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations. There are more than twenty types of neurotransmitter transporters.

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A neurotransmitter sodium symporter (NSS) (TC# 2.A.22) is type of neurotransmitter transporter that catalyzes the uptake of a variety of neurotransmitters, amino acids, osmolytes and related nitrogenous substances by a solute:Na+ symport mechanism. The NSS family is a member of the APC superfamily. Its constituents have been found in bacteria, archaea and eukaryotes.

<span class="mw-page-title-main">GABA transporter type 1</span> Protein-coding gene in the species Homo sapiens

GABA transporter 1 (GAT1) also known as sodium- and chloride-dependent GABA transporter 1 is a protein that in humans is encoded by the SLC6A1 gene and belongs to the solute carrier 6 (SLC6) family of transporters. It mediates gamma-aminobutyric acid's translocation from the extracellular to intracellular spaces within brain tissue and the central nervous system as a whole.

In biochemistry, the glutamate–glutamine cycle is a cyclic metabolic pathway which maintains an adequate supply of the neurotransmitter glutamate in the central nervous system. Neurons are unable to synthesize either the excitatory neurotransmitter glutamate, or the inhibitory GABA from glucose. Discoveries of glutamate and glutamine pools within intercellular compartments led to suggestions of the glutamate–glutamine cycle working between neurons and astrocytes. The glutamate/GABA–glutamine cycle is a metabolic pathway that describes the release of either glutamate or GABA from neurons which is then taken up into astrocytes. In return, astrocytes release glutamine to be taken up into neurons for use as a precursor to the synthesis of either glutamate or GABA.

<span class="mw-page-title-main">GABA reuptake inhibitor</span> Drug class

A GABA reuptake inhibitor (GRI) is a type of drug which acts as a reuptake inhibitor for the neurotransmitter gamma-Aminobutyric acid (GABA) by blocking the action of the gamma-Aminobutyric acid transporters (GATs). This in turn leads to increased extracellular concentrations of GABA and therefore an increase in GABAergic neurotransmission. Gamma-aminobutyric acid (GABA) is an amino acid that functions as the predominant inhibitory neurotransmitter within the central nervous system, playing a crucial role in modulating neuronal activity in both the brain and spinal cord. While GABA predominantly exerts inhibitory actions in the adult brain, it has an excitatory role during developmental stages. When the neuron receives the action potential, GABA is released from the pre-synaptic cell to the synaptic cleft. After the action potential transmission, GABA is detected on the dendritic side, where specific receptors collectively contribute to the inhibitory outcome by facilitating GABA transmitter uptake. Facilitated by specific enzymes, GABA binds to post-synaptic receptors, with GABAergic neurons playing a key role in system regulation. The inhibitory effects of GABA diminish when presynaptic neurons reabsorb it from the synaptic cleft for recycling by GABA transporters (GATs). The reuptake mechanism is crucial for maintaining neurotransmitter levels and synaptic functioning. Gamma-aminobutyric acid Reuptake Inhibitors (GRIs) hinder the functioning of GATs, preventing GABA reabsorption in the pre-synaptic cell. This results in increased GABA levels in the extracellular environment, leading to elevated GABA-mediated synaptic activity in the brain.

Reverse transport, or transporter reversal, is a phenomenon in which the substrates of a membrane transport protein are moved in the opposite direction to that of their typical movement by the transporter. Transporter reversal typically occurs when a membrane transport protein is phosphorylated by a particular protein kinase, which is an enzyme that adds a phosphate group to proteins.

Anoxic depolarization is a progressive and uncontrollable depolarization of neurons during stroke or brain ischemia in which there is an inadequate supply of blood to the brain. Anoxic depolarization is induced by the loss of neuronal selective membrane permeability and the ion gradients across the membrane that are needed to support neuronal activity. Normally, the Na+/K+-ATPase pump maintains the transmembrane gradients of K+ and Na+ ions, but with anoxic brain injury, the supply of energy to drive this pump is lost. The hallmarks of anoxic depolarization are increased concentrations of extracellular K+ ions, intracellular Na+ and Ca2+ ions, and extracellular glutamate and aspartate. Glutamate and aspartate are normally present as the brain's primary excitatory neurotransmitters, but high concentrations activate a number of downstream apoptotic and necrotic pathways. This results in neuronal dysfunction and brain death.

GABA transporter 2 also known as sodium- and chloride-dependent GABA transporter 2 is one of four GABA transporters, GAT1 (SLC6A1), GAT2 (SLC6A13), GAT3 (SLC6A11) and BGT1 (SLC6A12). Note that GAT2 is different from BGT1 despite the fact that the latter transporter is sometimes referred at as (mouse) GAT-2.

References

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