Neurotransmitter transport

Neurotransmitter Transporters Monoamine Oxidases and their Inhibitors... 

Neurotransmitter transporters Members of the family of solute carriers Products of the (solute carrier) SLC1, SLC6, SLC17, SLC18, and SLC22 gene families... 

Neurotransmitter transporters create neurotransmitter gradients across membranes, which results in the uptake of the neurotransmitter. By working in reverse they can also release neurotransmitter into the extracellular space (efflux by nonexocytotic release). 

Substrate specificity is determined by high affinity for the cognate neurotransmitter substrate. However, low affinity uptake does also have a part in the clearance of transmitters from the interstitial space (e.g., in uptake mediated by the extraneuronal monoamine transporter, EMT) and in the intestinal absoiption of glycine and glutamate. It is obvious that there is an evolutionary relation of neurotransmitter transporters and amino acid and cation transporters in epithelia. 

Neurotransmitter transporters fulfill three fundamental functions. 

Neurotransmitter transporters determine the neurotransmitter concentration in the interstitium. High-affinity transporters can efficiently remove neurotransmitter from the extracellular space because cellular uptake is typically coupled to the translocation of sodium ions. 

Neurotransmitter transporters terminate the time interval of synaptic neurotransmission localization of transporters in the vicinity of exocytotic sites is crucial for their clearance of neurotransmitter molecules following their exocytotic release into the synaptic cleft. 

Neurotransmitter Transporters. Table 1 SLC1 family transporters for L-glutamate (and D/L-aspartate)... 

Neurotransmitter Transporters. Table 2 SLC6 family transporters for GABA (y-amino butyric acid) and glycine... 

Neurotransmitter Transporters. Table 3 SLC6 family transporters for monoamines... 

Neurotransmitter transport can be electrogenic if it results in the net translocation of electrical charge (e.g. if more cations than anions are transferred into the cell interior). Moreover, some transporters may direction-ally conduct ions in a manner akin to ligand-gated ion channels this ion flux is not coupled to substrate transport and requires a separate permeation pathway associated with the transporter molecule. In the case of the monoamine transporters (DAT, NET, SERT) the sodium current triggered by amphetamine, a monoamine and psychostimulant (see Fig. 4) is considered responsible for a high internal sodium concentration... 

Neurotransmitter Transporters. Figure 3 Dopamine turnover at a presynaptic nerve terminal, (a) Dopamine is produced by tyrosine hydroxylase (TH). When secretory vesicles are filled, they join the releasable pool of vesicles at the presynaptic membrane. Upon exocytosis, the diffusion of released dopamine is limited by reuptake via DAT. (b) If DAT is inactive, dopamine spreads in the cerebrospinal fluid but cannot accumulate in secretory vesicles. This results in a compensatory increase of dopamine hydroxylase activity and a higher extracellular dopamine level mice with inactive DAT are hyperactive. 

Neurotransmitter Transporters. Table 4 Clinically useful inhibitors of monoamine neurotransmitter transporters... 

Chen NH, Reith ME, Quick MW (2004) Synaptic uptake and beyond the sodium- and chloride-dependent neurotransmitter transporter family SLC6. Pfliigers Arch 447 519-531... 

Sitte HH, Freissmuth M (eds) (2006) Neurotransmitter transporters. Handbook of Experimental Pharmacology. Springer-verlag, Berlin Heidelberg, 175... 

Neurotransmitter Transporters Brain Derived Neurotrophic Factor Neurotrophic Factors Corticotropin Releasing Hormone CRH... 

Sialin was first identified as the product of the gene defective in sialidosis, a lysosomal storage disorder. The transporter mediates the movement of sialic acid out of lysosomes by coupling to the proton electrochemical gradient across the lysosomal membrane. Unlike the vesicular neurotransmitter transporters which are antiporters, sialin is a sympoiter with sialic acid and protons both moving out of the lysosome. 

Synaptic Transmission. Figure 1 Synaptic transmission. The presynaptic terminal contains voltage-dependent Na Superscript and Ca2+ channels, vesicles with a vesicular neurotransmitter transporter VNT, a plasmalemmal neurotransmitter transporter PNT, and a presynaptic G protein-coupled receptor GPCR with its G protein and its effector E the inset also shows the vesicular H+ pump. The postsynaptic cell contains two ligand-gated ion channels LGIC, one for Na+ and K+ and one for Cl-, a postsynaptic GPRC, and a PNT. In this synapse, released transmitter is inactivated by uptake into cells. 

Synaptic vesicle neurotransmitter transporters VMAT1 VMAT2 VGAT/VIAAT VGLUT1 VGLUT2 VGLUT3 VAChT... 

Synaptic vesicles isolated from brain exhibit four distinct vesicular neurotransmitter transport activities one for monoamines, a second for acetylcholine, a third for the inhibitory neurotransmitters GABA and glycine, and a fourth for glutamate [1], Unlike Na+-dependent plasma membrane transporters, the vesicular activities couple to a proton electrochemical gradient (A. lh+) across the vesicle membrane generated by the vacuolar H+-ATPase ( vacuolar type proton translocating ATPase). Although all of the vesicular transport systems rely on ApH+, the relative dependence on the chemical and electrical components varies (Fig. 1). The... 

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