The vesicular neurotransmitter transporters: current perspectives and future prospects.

There are three families of vesicular neurotransmitter transporters. The vesicular amine transporters (VATs) are members of the toxin-extruding protontranslocating antiporter family (TEXANs) (1). The vesicular inhibitory amino acid transporter (VIAAT/ VGAT) is a member of a second family with limited homology to plant amino acid permeases (2, 3). A vesicular transporter for the excitatory amino acid glutamate (VGlut) has been cloned and functionally characterized (4, 5), and is a member of a separate, third gene family. These three transporter families account for the vesicular transport of catecholamines, serotonin, histamine, acetylcholine, GABA, glycine, and glutamate. The vesicular neurotransmitter transporters (VNTs) are the final arbiters of neurotransmitter entry into the secretory vesicle: they specify the quality and quantity of its content. VNT targeting to specific types of vesicles determines the subcellular locations from which transmitters are mobilized and thus the synaptic dynamics of neurotransmission. Loss of chemical neurotransmission in nematodes deficient in vesicular transmitters and loss of transmitter release in cells cultured from VNT-deficient mice have provided reverse genetic proof of the vesicular hypothesis of neurotransmission (6, 7). Neurodegenerative processes as they occur during human life are being imaged with neurotransmitter transporter ligands (8). The chemical neuroanatomy of the vesicular transporters has revealed novel neuronal phenotypes and demonstrated the existence of amine-handling capability in inflammatory as well as neuroendocrine cells (9). Future prospects include elucidating gene regulatory mechanisms for cell-specific expression of the vesicular transporters; identifying novel proteins required for vesicular transporter targeting; and characterizing discrete classes of neurotransmitter release sites based on vesicular transporter targeting to several types of synaptic vesicle, required for the dynamic range of neurotransmission used by different neuronal subtypes. Vesicular neurotransmitter transporters are the gatekeepers of the secretory vesicle, responsible for regulated secretion of informational molecules from neurons (i.e., neurotransmitters) and neuroendocrine cells (i.e., hormones, paracrine, or autocrine factors). The history of the vesicular transporter field began with the discovery of neurotransmitter secretory vesicles themselves by Hillarp in 1958 (10), and several reviews have been written on the early development of the field, describing the isolation of catecholamine granules and cholinergic vesicles, development of pharmacological agents for the study of vesicular transport, and the biochemical characterization of the transport process itself (1, 11–18). The cloning of the vesicular amine transporters has revealed much about their involvement in neurotransmission and its regulation. Perhaps most important, vesicular transporters are no longer viewed as static filters for admitting a fixed amount of neurotransmitter into a fixed number of standard-sized vesicles, but as dynamic regulators of where, how, what kind, and how much neurotransmitter is released during synaptic transmission (19). The full extent of how the regulation of vesicular transporter activity fine-tunes neuronal and endocrine informational output is just now being delineated. Information obtained about the neuroanatomical localization and expression of vesicular transporters is reviewed here by Weihe and Eiden (9). The question of why two monoamine transporters should exist at all in mammals, for example, is answered by the observation that the VMAT1 isoform is restricted to endocrine cells and VMAT2 is the only form expressed in neurons, although VMAT2 is expressed in some neuroendocrine cells, depending on the species examined. A strict neuroendocrine division between VMAT1 and VMAT2 expression exists in the enterochromaffin cells of the gut in all species. Only VMAT1 is expressed in serotonin-accumulating enterochromaffin cells, whereas only VMAT2 is found in enterochromaffin-like histaminocytes of the stomach. The major difference between the two transporters is that VMAT2 efficiently transports histamine and VMAT1 does not. VMAT1 may have evolved during the evolutionary emergence of histamine as a secreted effector molecule, restricting the