br Functions essentially consisting in

Functions essentially consisting in transport of substrates across plasma membranes
Direct activation of neurotransmitter transporters elicits responses in neurons As previously mentioned (Section 2.1), nerve terminals handling classical transmitters possess transporters able to (re)capture selectively their messengers from the extracellular space. By modulating transmitter uptake, these transporters can determine the extracellular concentrations of neurotransmitters at pre- and postsynaptic receptors, thus regulating indirectly the excitability of neighboring neurons. However, besides this indirect mode of regulation, some transporters can affect neuronal excitability directly, through receptor-independent, transporter-mediated, presynaptic effects.
Transporter–transporter and transporter–receptor functional cross-talks on the same nerve terminal In the preceding part of the article, we have described functions of neurotransmitter transporters that are inherent in the carrier molecules and may occur independently of the interactions between transporters and other proteins coexpressed on the plasma membrane of the same terminal. Novel functions of neurotransmitter transporters can in fact originate from interactions between autotransporters and presynaptic receptors as well as between autotransporters and heterotransporters coexisting on the same nerve terminal. A number of these interactions had been previously identified (Raiteri et al., 2002), although the mechanisms underlying some of these interactions have only recently been clarified (see below) while others require further investigation. As recent examples of novel neurotransmitter transporter functions, we will here describe some functional interactions involving glycine transporters, GABA transporters, glutamate transporters and presynaptic NMDA glutamate receptors with their consequences in modulating neurotransmitter release.
Neurotransmitter transporters as receptor-like mediators of releasing stimuli A number of stimuli have been employed to evoke transmitter release during experiments in vitro. These include electrical stimulation of 1478 slices and addition to various nervous tissue preparations of compounds able to preferentially evoke release of one transmitter (for instance addition of amphetamine to evoke release of dopamine) or of agents that can stimulate release of all neurotransmitters, including KCl at elevated concentrations, 4-aminopyridine (4-AP) or veratridine. The results described in the present article show that neurotransmitter transporters can represent novel targets for releasing stimuli able to provoke efflux of transmitters through various mechanisms. These releasing stimuli can be provoked by a given transmitter acting at its own autotransporters and by the same transmitter acting at the same transporters localized as heterotransporters on different nerve terminals. The pathophysiological significance of the transporter-mediated transmitter release remains poorly understood. However, the findings that GABA, acting at concentrations corresponding to its high affinity uptake at GAT1 autotransporters (Section 3.3) or at GAT1 heterotransporters (see, for instance, Section 5.2.1), could stimulate multimodal release of GABA or of glycine, respectively, suggest that the transporter-mediated release could also be physiologically relevant and should be further investigated.
Concluding remarks The functions that neurotransmitter transporters can carry on have increased dramatically since their original duty of transmitter sweepers. Neurotransmitter transporters can modulate indirectly the activation of receptors. Portions of the transmitters recaptured into nerve terminals can be stored again and reutilized. Being bidirectional, transporters can mediate transmitter release in the inside-out direction by transporter reversal. Transporters can perform heteroexchange processes to produce the phenomenon of ‘indirectly acting drugs’. Some transporters can provide transmitters to nerve terminals that lack efficient synthesis. Transporter activation can originate ionic fluxes, especially Na+ influx, that can trigger multiple events, including inversion of plasmalemmal Na+/Ca2+ exchangers and activation of mitochondrial Na+/Ca2+ exchangers. Thus neurotransmitter transporters can behave as presynaptic receptors able to mediate releasing stimuli leading to transmitter efflux through multiple mechanisms. Transporter coexistence on the same nerve terminal is a surprisingly widespread phenomenon whose functional significance deserves further investigation. As a final consideration, the unsuspected involvement of neuronal neurotransmitter transporters in so many functions implies that the effects of transporter inhibitors administered in vivo are likely to be much more complex than expected, with transporters playing potential roles in multiple therapeutic approaches.