Abstract
BackgroundGlutamate is the major transmitter that mediates the principal form of excitatory synaptic transmission in the brain. It has been well established that glutamate is released via Ca2+-dependent exocytosis of glutamate-containing vesicles in neurons. However, whether astrocytes exocytose to release glutamate under physiological condition is still unclear.FindingsWe report a novel form of glutamate release in astrocytes via the recently characterized Ca2+-activated anion channel, Bestrophin-1 (Best1) by Ca2+ dependent mechanism through the channel pore. We demonstrate that upon activation of protease activated receptor 1 (PAR1), an increase in intracellular Ca2+ concentration leads to an opening of Best1 channels and subsequent release of glutamate in cultured astrocytes.ConclusionsThese results provide strong molecular evidence for potential astrocyte-neuron interaction via Best1-mediated glutamate release.
Highlights
Glutamate is the major transmitter that mediates the principal form of excitatory synaptic transmission in the brain
protease activated receptor 1 (PAR1)-induced glutamate release is mediated by Ca2+-activated anion channel (CAAC) It has been suggested that hippocampal astrocytes utilize an anion channel-dependent mechanism for Ca2+-induced glutamate release [10,16]
We found that an application of TFLLR induced a significant glutamate release from cultured astrocytes (Figure 1B), which was inhibited by a pre-incubation of anion channel blockers, such as niflumic acid and flufenamic acid (Figure 1B) [28]
Summary
Glutamate is the major transmitter that mediates the principal form of excitatory synaptic transmission in the brain. The synaptically released neurotransmitters such as glutamate and ATP activate corresponding Gαq protein-coupled receptors expressed in astrocytes, resulting in increase in [Ca2+]i and Ca2+-dependent release of gliotransmitters from astrocytes [2,3]. These gliotransmitters in turn influence the neuronal excitability and synaptic activities [3,4,5,6,7,8]. Bestrophin is the gene identified as the gene responsible for Best's vitelliform macular dystrophy and has been shown to encode a functional Ca2+-activated anion channel (CAAC) in nonneuronal tissue and peripheral neurons [17]. We demonstrate that PAR1-induced glutamate release is mediated not by conventional vesicular exocytosis but by an activation of glutamate permeable anion channel Best in cultured astrocytes
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