Abstract
The vesicular transmitter transporters VGLUT, VGAT, VMAT2 and VAChT, define phenotype and physiological properties of neuronal subtypes. VGLUTs concentrate the excitatory amino acid glutamate, VGAT the inhibitory amino acid GABA, VMAT2 monoamines, and VAChT acetylcholine (ACh) into synaptic vesicle (SV). Following membrane depolarization SV release their content into the synaptic cleft. A strict segregation of vesicular transporters is mandatory for the precise functioning of synaptic communication and of neuronal circuits. In the last years, evidence accumulates that subsets of neurons express more than one of these transporters leading to synaptic co-release of different and functionally opposing transmitters and modulation of synaptic plasticity. Synaptic co-existence of transporters may change during pathological scenarios in order to ameliorate misbalances in neuronal activity. In addition, evidence increases that transporters also co-exist on the same vesicle providing another layer of regulation. Generally, vesicular transmitter loading relies on an electrochemical gradient ΔμH+ driven by the proton ATPase rendering the lumen of the vesicle with respect to the cytosol positive (Δψ) and acidic (ΔpH). While the activity of VGLUT mainly depends on the Δψ component, VMAT, VGAT and VAChT work best at a high ΔpH. Thus, a vesicular synergy of transporters depending on the combination may increase or decrease the filling of SV with the principal transmitter. We provide an overview on synaptic co-existence of vesicular transmitter transporters including changes in the excitatory/inhibitory balance under pathological conditions. Additionally, we discuss functional aspects of vesicular synergy of transmitter transporters.
Highlights
Synaptic vesicles (SV) are key organelles for neuronal communication
Members account for the vesicular transport of monoamines (VMAT1 and VMAT2; SLC18A1, SLC18A2, respectively), acetylcholine (VAChT, SLC18A3), GABA/glycine (VGAT known as VIAAT, SLC32A1), and glutamate (VGLUT1-3; SLC17A7, SLC17A6, SLC17A8, respectively)
The specificity of the co-existence of VGAT with vesicular glutamate transporter (VGLUT) in mossy fiber terminals (MFTs) (Figure 1) is underscored by the complete absence of VGAT immunoreactivity in other glutamatergic terminals such as cerebellar parallel (VGLUT1-positive) and climbing (VGLUT2-positive) fiber terminals identified in the same section (Figure 1). These findings provide a strong morphological evidence for synaptic co-existence of glutamate and GABA in adult glutamatergic MFTs under healthy conditions
Summary
Synaptic vesicles (SV) are key organelles for neuronal communication. They concentrate neurotransmitters produced in neural cytoplasm. Following scenarios may apply to synaptic co-existence and co-release : (1) The VNTs reside on distinct populations of SVs in the axon terminal, indicating the potential for different release at distinct sites, which activate subsets of postsynaptic receptors (Figure 1) This principle may primarily apply to giant terminals containing many transmitter release sites such as the mossy fiber terminals (MFTs; Boulland et al, 2009). Postembedding immunogold EM is the method of choice to label precisely subcellular organelles, such as SV (Bergersen et al, 2008; Grønborg et al, 2010; Zander et al, 2010; Ormel et al, 2012) By this method, a synaptic co-localization of VGLUTs and VGAT in glutamatergic hippocampal and cerebellar MFTs could be demonstrated (Figure 1). It has been shown that amacrine cells in the retina co-release ACh and GABA by distinct SV populations (Lee et al, 2010)
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