Gliotransmitters are chemicals released from glial cells that facilitate communication between glial cells and neurons. They are usually induced from Ca2+ signaling, although recent research has questioned the role of Ca2+ in gliotransmitters and may require a revision of the relevance of gliotransmitters in neuronal signalling in general. While gliotransmitters can be released from any glial cell, they are primarily released from astrocytes. Astrocytes rely on gap junctions for coupling, and are star-like in shape, which allows them to come into contact with many other synapses in various regions of the brain. Their structure also makes them capable of bidirectional signaling. It is estimated that astrocytes can make contact with over 100,000 synapses, allowing them to play an essential role in synaptic transmission. While gliotransmission primarily occurs between astrocytes and neurons, gliotransmission is not limited to these two cell types. Besides the central nervous system, gliotransmission also occurs among motor nerve terminals and Schwann cells in the peripheral nervous system. Another occurrence of gliotransmission takes place between glial cells in the retina, called Müller cells, and retinal neurons.
Function The word “glia”, derived from the Greek words γλία and γλοία ("glue"), illustrates the original belief among scientists that these cells play a passive role in neural signaling, being responsible only for neuronal structure and support within the brain. Glial cells cannot produce action potentials and therefore were not suspected as playing an important and active communicative role in the central nervous system, because synaptic transmission between neurons is initiated with an action potential. However, research shows that these cells express excitability with changes in the intracellular concentrations of Ca2+. Gliotransmission occurs because of the ability of glial cells to induce excitability with variations in Ca2+ concentrations. Changes in the concentration of Ca2+ correlate with currents from NMDA receptor-mediated neurons which are measured in neighboring neurons of the ventrobasal (VB) thalamus. Because glial cells greatly outnumber neurons in the brain, accounting for over 70% of all cells in the central nervous system, gliotransmitters released by astrocytes have the potential to be very influential and important within the central nervous system, as well as within other neural systems throughout the body. These cells do not simply carry out functions of structural support, but can also take part in cell-to-cell communication with neurons, microglia, and other astrocytes by receiving inputs, organizing information, and sending out chemical signals. The Ca2+ signal from the astrocyte may also participate in controlling blood flow in the brain. Gliotransmitters have been shown to control synapse development and regulate synaptic function, and their release can lead to paracrine actions on astrocytes as well as the regulation of neurotransmission. The definition of a gliotransmitter is not only defined by its presence in glial cells, but is determined by other factors, including its metabolic pathway. Also, the function of gliotransmitters varies according to their type, and each gliotransmitter has a specific target receptor and action. Glial cells are important in hormonal and neuroendocrine function in the central nervous system and have an active role in sleep, cognition, synaptic function and plasticity, and promote remyelination and regeneration of injured nervous tissue. Other functions include the regulation of neurosecretory neurons and the release of hormones.
Types of gliotransmitters The major types of gliotransmitters released from astrocytes include glutamate and ATP. Glutamate is the major excitatory neurotransmitter within the central nervous system that can also be defined as a gliotransmitter due to its ability to increase cytosolic Ca2+ concentrations in astrocytes. Its main target receptors include Kainate receptors, metabotropic glutamate receptors (mGluRs), and especially N-methyl D-aspartate receptors (NMDARs). NMDARs are glutamatergic receptors that play an important role in synaptic plasticity. Other functions of this gliotransmitter include synchronous depolarization, increasing the frequency of postsynaptic currents, and also increasing the likelihood of release and frequency of AMPA-receptor-dependent postsynaptic currents NMDARs are controlled by a voltage-gated channel receptor that is blocked by magnesium. Calcium can enter through NMDAR channels due to the cell's depolarization, which removes the magnesium block, and therefore activating these receptors. ATP is a gliotransmitter that is released from astrocytes and restrains neuronal activity. ATP targets P2X receptors, P2Y, and A1 receptors. ATP has several functions as a gliotransmitter, including insertion of AMPA receptors into the postsynaptic terminal, paracrine activity through calcium waves in astrocytes, and suppression of synaptic transmission. Neuronal activity is controlled in the retina by the molecule's ability to hyperpolarize the neuron by converting from ATP to adenosine. ATP plays a role in facilitating neuroinflammation and remyelination by entering into the cell's extracellular space upon injury to activate purinergic receptors, which increase the production of gliotransmitters. The mechanism of ATP release from astrocytes is not well understood. Although it is unclear whether or not ATP-mediated gliotransmission is calcium-dependent, it is believed that ATP release is partly dependent on Ca2+ and SNARE proteins and involves multiple pathways, with exocytosis being the suggested method of release. Other less common gliotransmitters include:
homocysteic acid, an endogenous N-methyl-(D)-aspartic acid receptor (NMDAR) agonist taurine atrial natriuretic factor (ANF) tumor necrosis factor-alpha (TNF-alpha) GABA.
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