Disease relevance of SLC22A3

• Summarizing, we firstly describe a marked and highly confined expression of the extraneuronal monoamine transporter in the rat area postrema by in situ hybridisation which may play a role in physiological functions of this circumventricular organ such as emesis, food intake and the regulation of cardiovascular functions [1].
• SarCNU demonstrates selective cytotoxicity in vitro against human glioma at least in part because of the selective SarCNU uptake by the extraneuronal monoamine transporter [2].
• These studies provided a new insight into the signaling mechanism underlying the apoptosis and EMT, which could be of importance in understanding some related physiologic and pathologic processes [3].
• Four tumor types implanted in the brain or subcutis in nude mice were studied: a murine rhabdomyosarcoma (M1S), a murine mammary carcinoma (EMT), and two human glioblastomas (U87 and U251) [4].
• PURPOSE: OCT4 (POU5F1, OCT3) immunostaining highlights pluripotent cells (embryonal carcinoma and seminoma) in primary testicular germ cell tumors, but its relative usefulness in diagnosing intratubular germ cell neoplasia, unclassified (IGCNU) is not well established [5].

Psychiatry related information on SLC22A3

• Moreover, SLC22A3 (which encodes OCT3) is a candidate gene for MAP dependence because it is located within a chromosomal region associated with substance dependence [6].

High impact information on SLC22A3

• Secondary crosslinking of CD28 is unnecessary for the induced tyrosine phosphorylation of p72ITK/EMT [7].
• Thus, tyrosine phosphorylation of p72ITK/EMT may represent one of the earliest events in CD28 signaling [7].
• CD28 is associated with and induces the immediate tyrosine phosphorylation and activation of the Tec family kinase ITK/EMT in the human Jurkat leukemic T-cell line [7].
• Apoptosis and epithelial-to-mesenchymal transdifferentiation or transition (EMT) are crucial for normal development and body homeostasis [3].
• In contrast, OCT3 did not mediate choline transport [8].

Chemical compound and disease context of SLC22A3

• (6) The consistent factor associated with EMT was only high-GOP solution (60 patients, n = 178, beta coefficient 0.312, p = 0.000; 46 patients, n = 137, beta coef: 0.228, p = 0.000) and not numbers of peritonitis episodes, duration of angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker medication, or diabetes [9].

Biological context of SLC22A3

• SLC22A3 is expressed in first-trimester and term placenta, but also in skeletal muscle, prostate, aorta, liver, fetal lung, salivary gland, and adrenal gland [10].
• Cloning of the mouse and human solute carrier 22a3 (Slc22a3/SLC22A3) identifies a conserved cluster of three organic cation transporters on mouse chromosome 17 and human 6q26-q27 [10].
• Using a somatic cell hybrid panel and a human YAC clone, SLC22A3 was mapped to the syntenic region on human chromosome 6q26-q27, between the IGF2R and APO(a)-like genes [10].
• Famotidine exhibited potent inhibition of hOCT3; in contrast, ranitidine was a moderately weak inhibitor (IC50= 6.7 and 290 microM, respectively) [11].
• Inhibition and substrate specificity of hOCT1, hOCT2, and hOCT3 for ranitidine and famotidine were elucidated in cRNA-injected Xenopus laevis oocytes [11].

Anatomical context of SLC22A3

• To examine whether some cell lines express several different OCTs, we investigated seven human cell lines for the mRNA expression pattern of the human (h) transporters hOCT1, hOCT2 and hOCT3. hOCT1 mRNA was found in all cell lines, six additionally expressed hOCT3 and only two cell lines contained all three hOCTs [12].
• Regional distribution studies with in situ hybridization show that OCT3 is expressed widely in different brain regions, especially in the hippocampus, cerebellum, and cerebral cortex [13].
• Non-neuronal monoamine transporters OCT1, OCT2, and EMT, which are all members of the amphiphilic solute facilitator family, control signal transmission by removing released transmitters, such as dopamine, noradrenaline, adrenaline, 5-hydroxytryptamine, and histamine, from the extracellular space [14].
• Using an in situ hybridization to the rat brain, we detected a marked and highly confined expression of the extraneuronal monoamine transporter in the area postrema, but in no other brain areas [1].
• These findings were confirmed by polyclonal antibodies against rat extraneuronal monoamine transporter showing an intensive signal in the area postrema, although a few cells in the cerebellum and the brain stem also showed a signal [1].

Associations of SLC22A3 with chemical compounds

• Famotidine seems to be one of the most potent inhibitors of hOCT3 yet identified [11].
• Corticosterone was about 100 fold more potent as inhibitor of hOCT3 than of hOCT1 or hOCT2, and O-methylisoprenaline (OMI) inhibited almost exclusively hOCT3 [12].
• Decynium-22 inhibited hOCT3 with 10 fold higher potency than hOCT1 and hOCT2 [12].
• Progesterone and beta-Oestradiol preferentially inhibited hOCT3 and hOCT1, whereas prazosin was a potent inhibitor of hOCT1 and hOCT3 [12].
• Phenoxybenzamine (PbA) inhibited with about equal apparent potency all three hOCTs, whereas the PbA derivative SKF550 ((9-fluorenyl)-N-methyl-beta-chloroethylamine) preferentially inhibited hOCT3 and hOCT2 [12].

Other interactions of SLC22A3

• SLC22A2 and SLC22A3, two genes downstream of IGF2R that are imprinted in the mouse, showed no T1D association [15].
• Modeling analyses predicted multiplicity of the uptake mechanisms with the high-affinity systems characterized by K(m) of 5.1 microM for carnitine and 1.6 mM for TEA, apparently similar to the reported hOCTN2 parameter for carnitine, and that of EMT/hOCT3 for TEA [16].
• The EMT gene is 77 kb, and the OCT2 gene is 45 kb in size [14].
• Cultures were pretreated with either corticosterone, a specific inhibitor of EMT, or reserpine, a specific inhibitor of VMAT-2 [17].
• The EMT promoter, located within a CpG island, lacks a consensus TATA box but contains a prototypical initiator element and a number of potential binding sites for ubiquitous transcription factors Sp1 and NF-1 [14].

Analytical, diagnostic and therapeutic context of SLC22A3

• For the EMT gene, two transcription start points were identified by inverse polymerase chain reaction based on mRNA from Caki-1 cells [14].
• Moreover, quantitative analysis showed a significant lower expression of NET and EMT mRNAs in pre-eclamptic placentae as compared to the control group [18].
• The expression of OCT3 in human kidney was confirmed by RT-PCR [19].
• TGF-beta1-induced apoptosis and EMT were associated with the activation of protein kinase A (PKA) and signal transducers and activators of transcription 3 (STAT3) [3].
• The present study demonstrates the usefulness of OCT3/4 immunohistochemistry in a diagnostic setting of a consecutively collected series of more than 200 testicular tumours and over 80 testicular biopsies [20].

References