6). and glial fibrillary acidic protein (GFAP) revealed that mPMAT is usually expressed in neuronal cells but not in astrocytes. mPMAT is usually co-expressed in many brain regions with the high affinity 5-HT transporter (SERT) and the dopamine transporter (DAT), but is also found in certain sites that receive monoamine innervation but lack significant expression of SERT or DAT. These findings suggest that mPMAT is usually a widely distributed, neuronally-expressed transporter, which may support the role of 5-HT and DA uptake under certain conditions. hybridization, 5-HT, dopamine In the CNS, the monoamine neurotransmitters 5-HT, dopamine (DA), and norepinephrine (NE) control a variety of physiological, behavioral, and endocrine functions (Carlsson, 1987; Greengard, 2001). Monoamines are also critically involved in the pathophysiology and pharmacotherapy of a number of brain disorders, including Parkinsons disease, depressive disorder, schizophrenia, and drug Rabbit polyclonal to ITPK1 dependency (Carlsson, 1987; Greengard, 2001; Gainetdinov et al., 2002). The plasma Dimethocaine membraneCexpressed transporters for 5-HT, DA, and NE play a key role in determining the intensity and duration of monoamine signaling by removing these transmitters from the extracellular space (Iversen, 1971; Blakely et al., 1994; Torres et al., 2003). Dimethocaine Uptake of released monoamines into presynaptic neurons is mainly carried out by a family of Na+- and Cl?-dependent high affinity plasma membrane transporters, which include the dopamine transporter (DAT), the 5-HT transporter (SERT), and the norepinephrine transporter (NET). These high affinity transporters, also known as uptake1, share high sequence similarity and belong to the solute carrier 6 (SLC6) family. In the CNS, DAT, SERT and NET are expressed almost exclusively in the nerve terminals of monoaminergic neurons, and they represent the major targets of many psychotropic drugs and neurotoxins (Amara and Kuhar, 1993; Blakely et al., 1994; Torres et al., 2003). In addition to uptake1, a Na+- and Cl?-impartial, low-affinity, high-capacity transport system, termed uptake2, was recognized and first characterized in peripheral tissues (Lightman and Iversen, 1969; Iversen, 1971; Eisenhofer, 2001). Uptake2 displays different pharmacological profiles from uptake1, and is thought to play a role in catecholamine removal in peripheral tissues with sympathetic innervation (Lightman and Iversen, 1969; Iversen, 1971; Eisenhofer, 2001). In the CNS, a number of studies have described uptake2-like monoamine transport activities in tissue preparations from various brain areas including the cortex, striatum and accumbal tissues (Hendley et al., 1970; Burrows et al., 1981; Mireylees et al., 1986; Inazu et al., 1999). Recent studies in brain tissues from DAT and SERT knock-out mice also provided evidence of the presence of monoamine uptake activities that cannot be fully explained by the presence of high affinity transporters (Mundorf et al., 2001; Ravary et al., 2001; Sora et al., 2001; Wayment et al., 2001). However, in contrast to the well-characterized high affinity transporters, the role of the low affinity transporters in CNS neurotransmission is still unknown. Recent molecular cloning work has identified that organic cation transporter 3 (OCT3) in the SLC22 family represents one of the uptake2 transporters for biogenic amines (Grundemann et al., 1998; Wu et al., 1998). Human OCT3 favors epinephrine and NE over Dimethocaine 5-HT and DA (Grundemann et al., 1998; Amphoux et al., 2006), and is broadly expressed in a number of tissues, including the liver, heart, placenta, skeletal muscle, kidney, and brain (Grundemann et al., 1998; Wu et al., 2000). In 2004, our laboratory reported the cloning and characterization of a novel uptake2-type transporter in the human brain, which we termed Dimethocaine plasma membrane monoamine transporter (PMAT) (Engel et al., 2004). The 530-residue human plasma membrane monoamine transporter (hPMAT) protein is not homologous to uptake1 transporters or the OCTs, but exhibits low sequence homology (~20% identity) to members in the equilibrative nucleoside transporter family (SLC29). We previously exhibited that PMAT, also alternatively termed equilibrative nucleoside transporter 4 (ENT4), exhibits typical uptake2 characteristics, mediating Na+ and Cl? impartial, low affinity and high capacity transport of monoamine neurotransmitters (Engel et al., 2004). Among the monoamines, PMAT favors 5-HT and DA over NE, epinephrine.