Co-existence of Functionally Different Vesicular Neurotransmitter Transporters

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.

Activation of Pyramidal Neurons in Mouse Medial Prefrontal Cortex Enhances Food-Seeking Behavior While Reducing Impulsivity in the Absence of an Effect on Food Intake

“…Nine out of ten cells expressed either VGLUT1 or VGLUT2, or both (Figure 1C ). The presence of these transporters is indicative of an excitatory, glutamatergic phenotype, as VGLUT is required to load synaptic vesicles with glutamate (Münster-Wandowski et al, 2016 ). Interestingly, we also found that some of these cells expressed mRNA for the markers GAD65, GAD67, PARV, SOM, and vasoactive intestintal peptide (VIP).…”

“…Overall, our observations indicate significant molecular diversity among the pyramidal cell population of the mPFC. The co-expression of VGLUT and GAD in mPFC PN is likely important for proper execution of mPFC function (Münster-Wandowski et al, 2016 ). It is possible that the diverse pyramidal subtypes subserve different components of the behaviors we have assessed.…”

The therapeutic importance of acid-base balance

“…Neuronal activity presents a substantial challenge to local acid-base balance. Neurotransmitter-filled vesicles release H + into the synaptic cleft [92] , [93] (H + themselves may be considered to be neurotransmitters [94] ) and are removed from the synaptic cleft by H + -coupled neurotransmitter transporters such as the excitatory amino acid transporter EAAT1. GABA-activated anion channels in neurons and astrocytes release HCO 3 – [95] , [96] , and the Ca 2+ /H + exchange activity of the plasma membrane Ca 2+ -ATPase (PMCA) in neurons causes a rise in extracellular pH as it restores intracellular Ca 2+ following an action potential [97] .…”

Ketone Bodies as Anti-Seizure Agents

“…Vesicular glutamate transporters are comprised of three homologous proteins (VLUT1-3) localized to functionally distinct populations of glutamatergic neurons [46]. VGLUTs utilize a proton electrochemical gradient to carry glutamate into synaptic vesicles, and the efficiency of this inward transport is maximized by low concentrations of the chloride anion [47].…”