Monoamine transporters family

Tricyclic antidepressant A family of first-generation (typical) antidepressants with a three-ringed structure that inhibit the action of monoamine transporters. 

Eiden, L. E., Schafer, M. K.-H., Weihe, E. and Schiitz, B. The vesicular amine transporter family (SLC18) amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine. Eur. J. Physiol. 447 636-640, 2004. 

Fig. 1). These monoamine transporters belong to the SLC6 gene family of Na -Cl"-coupled neurotransmitter transporters that is also referred to as the neurotransmitter sodium symporter (NSS) family (Chen et al., 2004). In addition to the monoamine transporters, the NSS family includes subfamilies of transporters for GABA, amino acids, creatine, and the osmolytes betaine and taurine (Chen et al., 2004). 

Several genetic polymorphisms have been identified for the genes encoding the monoamine transporters. A brief review of these genetic variations and possible associations with disease states is presented below and in Table 1. A comprehensive review by Hahn and Blakely examines the impact of genetic variations of the SLC6 gene family (Hahn and Blakely, 2007). 

The neurotransmitter transporter family has provided many valuable targets for psychopharmacology. There is every prospect that this will continue. It might seem that the monoamine transporters had already been fully exploited, but the reemergence of NET-specific antidepressants and the possible applications of selective inhibitors of DAT suggest that there may still be room for innovation even in such a crowded field. 

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

As with other monoamines, the actions of 5-HT are terminated by its reuptake from the synapse by another member of the family of Na+/CU-dependent transporters. The 5-HT transporter has many features in common with its catecholamine equivalent (described fully in Chapter 8 see Fig. 8.7), including its presumed 12 transmembrane-spanning domains. However, the cloned 5-HT transporter has a for 5-HT of about 450 nM whereas its K for both noradrenaline and dopamine is some ten thousand-fold greater (Povlock and Amara 1997) which means that it is relatively selective for uptake... 

The DAT, NET, and SERT are members of the family of Na+, Cl -dependent substrate-specific neuronal membrane transporters, which includes transporters for GABA, glycine, taurine, proline, betaine, and creatine (4-8). The putative structure of these transporters consists of 12 transmembrane domains with both the N- and C-terminal domains located within the cytoplasm. The mechanism of the transporter-mediated uptake of monoamines is believed to involve an electrogenic transport of monoamines by sequential binding and cotransport of Na+ and Cl-ions (4-8). 

In the late 1970s a substantial clue to the cause of the nerve cell destruction in Parkinson s disease was provided by young drug addicts using the synthetic heroin substitute MPPP (l-methyl-4-phenyl-4-proprionoxypiperidine) (Figure 14B). Several unfortunate individuals, later found to have consumed MPPP, were diagnosed with Parkinson s disease despite their youth and lack of a family history of the disease. Considerable research revealed that under certain reaction conditions the synthesis of MPPP produces a toxic by-product called MPTP (l-methyl-4-phenyl-l,2,3,6-tetrahy-dropyridine). Once it has been consumed, MPTP is converted to MPP+ (l-methyl-4-phenylpyridinium) in the brain by the enzyme monoamine oxidase. After its synthesis, MPP+ is transported by a... 

In the disorder that was first observed in the Hailnup family and bears their name, the intestinal and renal transport defect involves the neutral amino acids (monoamine, monocarboxylic acids), including a number of the essential amino acids (isoleucine, leucine, phenylalanine, threonine, tryptophan, and valine) as well as certain nonessential amino acids (alanine, serine, and tyrosine). A reduction in the availability of these essential amino acids would be expected to cause a variety of clinical disorders. Yet children with the Hartnup disorder identified by routine newborn urine screening almost always remain clinically normal. 

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