Neurotransmitter 2015; 2: e491. doi: 10.14800/nt.491; © 2015 by Jonathan Stephan http://www.smartscitech.com/index.php/nt
REVIEW
Heterogeneous distribution and utilization of inhibitory neurotransmitter transporters Jonathan Stephan Animal Physiology Group, Department of Biology, University of Kaiserslautern Erwin Schroedinger-Strasse 13, D-67663 Kaiserslautern, Germany Correspondence: Jonathan Stephan E-mail:
[email protected] Received: December 23, 2014 Published online: February 1, 2015
Neurotransmitter homeostasis is important for proper synaptic signal transmission. Synaptically released neurotransmitters are recycled by direct reuptake into the presynaptic terminal and/or uptake into perisynaptic astrocyte processes. In the latter case, most neurotransmitters are metabolized and shuttled back to the presynaptic terminal to restore the neurotransmitter content in that compartment. In various regions of the central nervous system (CNS), the neurotransmitters glycine and GABA are heterogeneously utilized for inhibition of neuronal activity – glycine predominantly in caudal regions, GABA predominantly in rostral ones. Accordingly, respective transporters are used in neurons and astrocytes. Both cell types utilize different members of the neurotransmitter transporter family in a region-dependent manner. While glycine transporter (GlyT) 1 is predominantly utilized in astrocytes, GlyT2 is prevailing in neurons. The GABA transporters (GAT)-1 and -3 are not distinctly attributed to neurons or astrocytes, and transporter localization depends on the CNS region. Additionally, there is a complex interplay of different neurotransmitters and respective transporters as the uptake of one neurotransmitter into neurons as well as astrocytes can trigger the release of other transmitters from both cell types. This review summarizes the heterogeneous distribution and utilization of the four inhibitory neurotransmitter transporters GlyT1, GlyT2, GAT-1, and GAT-3 in olfactory bulb, retina, cortex, hippocampus, cerebellum, brainstem, thalamus, and spinal cord. Furthermore, it elaborates possible functional consequences of the transporter interplay for neurotransmitter homeostasis. Keywords: GlyT1; GlyT2; GAT-1; GAT-3; neurons; astrocytes To cite this article: Jonathan Stephan. Heterogeneous distribution and utilization of inhibitory neurotransmitter transporters. Neurotransmitter 2015; 2: e491. doi: 10.14800/nt.491.
GABA via inhibitory neurotransmitter transporters causes an inward current [3, 5-9] and concomitant depolarization [7].
Introduction The inhibitory neurotransmitter transporters GlyT1, GlyT2, GAT-1, and GAT-3 belong to the solute carrier family 6 (Slc6). They are composed of 12 transmembrane segments and transporter-specific N- and C-terminal domains (Figure 1A). Each transporter is electrogenic and three of them share the same stoichiometry (Na+ : Cl- : Glycine/GABA): GlyT1 (Slc1A9; 2 : 1 : 1), GlyT2 (Slc1A5; 3 : 1 : 1), GAT-1 (Slc1A1; 2 : 1 : 1), and GAT-3 (Slc1A11; 2 : 1 : 1; Figure 1B) [1-4]. Thus, the uptake of glycine or
Glycine-mediated inhibition is predominant in brainstem and spinal cord, whereas GABA-mediated inhibition takes is prevalent in rostral brain regions. Nevertheless, the composition of inhibitory neurotransmitter transporters and their specificity for distinct cell types depends on the brain region [10-12]. GlyT1 and GAT-3 have long been considered to be located in astrocytes, whereas GlyT2 and GAT-3 were postulated to be utilized in neurons. However, results from in
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Neurotransmitter 2015; 2: e491. doi: 10.14800/nt.491; © 2015 by Jonathan Stephan http://www.smartscitech.com/index.php/nt
Figure 1. Topology and stoichiometry of inhibitory neurotransmitter transporters. A: Inhibitory neurotransmitter transporters exhibit 12 membrane spanning helices. N- and C-termini are located intracellularly. Differences between N- and C-termini of different transporters, which give rise to multiple regulatory domains, are neglected. B: All four inhibitory neurotransmitter transporters are secondary active and their transport activity mainly depends on the electrochemical Na+ gradient. GlyT1, GAT-1, and GAT-3 are electrogenic and exhibit the same stoichiometry (Na+ : Cl- : Glycine/GABA): 2 : 1 : 1. GlyT2 more strongly depends on the Na+ gradient (3 : 1 : 1).
situ hybridization and immunohistochemistry levels did not reveal conclusive evidence for cell type specificity. Meanwhile, the initially proposed distribution of inhibitory neurotransmitter transporters has been challenged, and a high heterogeneity regarding cell type specificity of GlyTs and GATs was frequently shown (Table 1). For a detailed analysis of cell type-specific utilization of respective transporters, different techniques are used: Whole-cell patch-clamp, immunohistochemistry, electron microscopy, or uptake/release assays using [3H]-labeled glycine or GABA. Functional analysis is done in acute tissue slices, freshly isolated cells, primary neuronal and astrocytic cultures, synaptosomes, gliosomes, and heterologous expression systems (Table 1). Properties of inhibitory neurotransmitter transporters The transport activity of the four secondary active inhibitory neurotransmitter transporters mainly depends on the Na+ gradient across the membrane (Figure 1). Taking the different stoichiometry of the transporters into account, only GlyT1, GAT-1, and GAT-3 are able to work bidirectionally under physiological conditions, whereas GlyT2 exclusively mediates glycine uptake [13, 14]. In addition to Na+, the transport requires all co-substrates. Consequently, GlyT1 activity depends on [Na+]i/o, [Cl-]i/o, and [Gly]i/o as well as the membrane potential EM [2, 5, 7]. Because of the similar stoichiometry, GAT activity similarly depends on [Na+]i/o, [Cl-]i/o, [GABA]i/o, and EM [3, 7-9, 15-19]. In comparison to neurons, astrocytes exhibit elevated [Na+]i and [Cl-]i of about 17mM and 30mM, respectively [20]. Together with [Gly]i and [GABA]i of about 2mM, respectively, astrocytes promote GlyT1 and GAT reversal under physiological conditions [14, 20, 21] . Interference of neurotransmitter transporters
inhibitory synaptic transmission and postsynaptic signal integration [22]. Transporter regulation not only depends on ion and neurotransmitter gradients [18], but can also be achieved via intracellular signaling [23, 24] through interaction with N- and C-termini of the transporters [25, 26]. Furthermore, as the reversal potential of GlyT1 and GATs is close to the resting EM of astrocytes under physiological conditions those transporters can be easily forced into reverse mode by increasing [Na+]i, [Cl-]i, [transmitter]i, or depolarization of the cell (cf. Figure 2) [17, 20]. Thus, astrocytes can directly serve tonic inhibition of neuronal network activity [27, 28].For reviews on tonic and phasic inhibition, see [29, 30]. Furthermore, as glycine is a co-agonist of NMDA receptors, it can directly modulate glutamatergic synaptic transmission. GlyT1-mediated release of glycine has been shown to alter NMDA receptor-mediated signaling [13, 31]. Inhibition of GlyT1-mediated glycine uptake was shown to facilitate NMDA receptor-mediated currents and long-term potentiation as well as axonal sprouting [32, 33]. Regarding GABA release, not only activation of ionotropic GABAA receptors is of interest, but also activation of the high-affinity metabotropic GABAB receptors. Indeed, regulation of GAT activity modulates GABAB receptor function [34]. Besides regulated neurotransmitter transporter-mediated uptake and release, the interplay of different neurotransmitters can have manifold effects. The most obvious interplay of two neurotransmitters takes place at mixed inhibitory synapses, which co-release glycine and GABA. Such synapses are present in various CNS regions, e.g. cerebellum, brainstem, and spinal cord [35-42]. Here, two mechanisms can lead to neurotransmitter release: 1) vesicle fusion and 2) transporter reversal. In presynaptic terminals, glycine and GABA concur on the binding site of the vesicular inhibitory amino acid transporter (VIAAT), which mediates the filling of vesicles with both neurotransmitters, depending on the ratio of available neurotransmitters [42] .
The regulation of neurotransmitter uptake modulates
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Neurotransmitter 2015; 2: e491. doi: 10.14800/nt.491; © 2015 by Jonathan Stephan http://www.smartscitech.com/index.php/nt Table 1. Distribution of inhibitory neurotransmitter transporters within the CNS. Region Olfactory bulb
Cell type A
Transporter / Method / Reference GlyT1 GlyT2
N
Retina
Cortex
MC
Fixed tissue, culture; IHC
[49, 50]
N
Fixed tissue; IHC, EM Fixed slices, cultures; IHC, EM
[51, 52]
A
N
Hippocampus
A
N
Cerebellum
Thalamus
Fixed slices; IHC
BG
Fixed slices, synaptosomes; IHC, EM, [3H]Glycine Fixed slices; IHC, EM, in situ hybridization Fixed slices, Synaptosomes; IHC, EM, [3H]Glycine
Acute slices, PC
[52, 53]
Ventral respiratory group(Ventrolateral medulla) Spinal cord
Acute slices; PC
[54]
[54]
Fixed slices; IHC, EM Fixed slices; IHC, EM
[55-58]
Acute slices; PC Fixed slices; IHC, EM Fixed slices; IHC, EM
Acute slices; PC
[9, 63]
Acute slices, PC (?) Fixed slices; IHC, EM
[8]
Acute slices; PC Fixed slices; IHC, EM
[68]
Acute slices; PC
[7]
[53]
[52, 64]
Fixed slices, synaptosomes; IHC, [3H]Glycine
[48, 65]
Acute slices; PC
[9, 63]
[19]
[5]
Cultures; [3H]GABA Acute slices, PC
[5]
Fixed slices; IHC
[10]
Acute slices, PC (?)
Fixed slices, synaptosoms; IHC, [3H]Glycine
Fixed slices; IHC Acute slices; PC
[7]
Acute slices; PC Fixed slices; IHC
[70]
N
N
[15]
Fixed slices; IHC
A
Fixed slices; IHC, EM Fixed slices synaptosomes; IHC, EM, [3H]GABA
Fresh isolation; IHC, PC
[52, 53, 62]
[61]
A
[15]
[48]
Synaptosomes; [3H]Glycine
N A
[53]
[47]
Fixed slices; IHC
N
A
Cultures, fixed slices; IHC
GAT-3 [47]
[52, 61]
N Brainstem Auditory BS
[48]
GAT-1 Fixed slices; IHC, in situ hybridization Fixed slices; IHC, in situ hybridization Fresh isolation; IHC, PC
[52] [52, 73, 74]
[45, 48, 61, 67]
[55-58]
[8]
Fixed slices, synaptosoms, IHC, EM Acute slices; PC
[45, 66]
Fixed slices; IHC, EM
[55]
Acute slices; PC
[7]
[68]
[55, 58-60] [58, 59]
[66]
[55]
[10, 48]
Fixed slices; IHC
[48, 69]
Fixed slices; IHC,in situ hybridization Gliosomes; IHC
[71, 72]
Fixed slices, synaptosomes; IHC, [3H]GABA
[48, 74]
[73]
Cell types: A: Astrocytes; BG: Bergmann glia; MC: Müller cells; N: Neurons; (?): Speculative results. Methods: EM: Electron microscopy; IHC: immunohistochemistry; PC: patch-clamp.
Glutamate uptake into these mixed inhibitory presynaptic terminals via neuron-specific glutamate transporters leads to production of GABA by degradation of glutamate via the glutamic acid decarboxylase (GAD) [37, 42, 43]. Consecutively, GABA can replace glycine at VIAAT, thus giving the synapse a more GABAergic phenotype, which alters the kinetics of inhibitory postsynaptic currents [37]. Besides altering the vesicular content, electrogenic glutamate uptake
(stoichiometry: 3Na+ : 1 glutamate : 1H+ against 1K+) [44] causing reduction of the electrical and Na+ gradient and synthesis of GABA - induces GAT reversal and consecutive GABA release [37, 43]. Additionally, GlyT2 activity in neurons can trigger GABA release via GAT reversal [45]. Thus, release of glycine and/or GABA depends on the distribution and amount of both neurotransmitters as well as the interplay of different transporters.
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Neurotransmitter 2015; 2: e491. doi: 10.14800/nt.491; © 2015 by Jonathan Stephan http://www.smartscitech.com/index.php/nt
Figure 2. Neurotransmitter dynamics. The scheme illustrates interference between released inhibitory and excitatory neurotransmitters. Release of glycine and GABA from inhibitory projections activates GlyRs and GABAARs at the postsynapse (1). Glycine and GABA are then taken up by GlyT1 and GATs into neighboring astrocytes (2), which causes an increase of [Gly]i, [GABA]i, [Na+]i, and [Cl-]i and a concomitant depolarization (3) due to the electrogenic nature of the transporters (cf. Figure 1). These intracellular alterations shift the reversal potential of GlyT1 causing a reversal of transport direction and glycine release at sites of low resting [gly]o (4) and may thereby modulate NMDARs at a nearby excitatory synapse (5) (cf. [13]). Excitatory terminals release glutamate activating AMPARs and NMDARs at the postsynapse (6). Glutamate is then taken up by astrocytic Glast (7), causing [Na+]i elevation and depolarization (8). Within the astrocyte, glutamate can be converted into GABA via GAD (9). GABA synthesis in combination with [Na+]i and [Cl-]i increase and concomitant depolarization (3, 8) after GlyT, GAT, and Glast activity (2, 7) can induce GAT reversal (10). Released GABA can now activate GABABRs at both inhibitory and excitatory presynaptic nerve terminals (11) and may thus modulate synaptic transmission. Direct recycling of released glycine and GABA by re-uptake, glycine shuttling via astrocytic GlyT1 and neuronal GlyT2, vesicle refilling via VIAAT, glutamate re-uptake, recycling via the glutamate-glutamine-cycle, and vesicle refilling via VGluT have been neglected for didactic reasons (cf. [13, 44]).
Conclusion Astrocytes in many brain regions simultaneously utilize GlyTs and GATs (cf. Table 1). As both neurotransmitter transporters are linked to the chemical gradient of Na+ and Cl- as well as astrocytic EM they can reciprocally reduce their activity [7]. Furthermore, uptake of glutamate into astrocytes after excitatory synaptic transmission can lead to production and release of GABA via GAT reversal (Figure 2) [43, 46]. Additionally, glycinergic synaptic transmission may trigger GABA release via GAT reversal as well (Figure 2). Independent from the possible effect of GAT activity on neuronal signaling, inhibitory glycinergic transmission will cause an increase of [Na+]i and [Cl-]i and depolarization of astrocytes, which subsequently enables glycine release via transporter reversal (Figure 2). If the release site is located near excitatory glutamatergic terminals, released glycine can act as a co-agonist on postsynaptic NMDA receptors and modulate synaptic transmission [13].
Both, the transport activity and the direction of neurotransmitter transport depend on the chemical (Na+, Cl-, glycine/GABA) and electrical gradient (EM) as well as transporter stoichiometry. Especially in astrocytes, which comprise higher [Na+]i and [Cl-]I than neurons [20], neurotransmitter transporters can reverse under physiological conditions and mediate transmitter release [14, 20]. The transporters are heterogeneously distributed within the CNS and utilized by both neurons and astrocytes (cf. Table 1) causing a brain region-dependent interplay. Conflict of interest The author declares that there are no conflicting interests. Acknowledgements Grant sponsor: Institutional funding
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Neurotransmitter 2015; 2: e491. doi: 10.14800/nt.491; © 2015 by Jonathan Stephan http://www.smartscitech.com/index.php/nt
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