Blood—Brain Barrier Genomics and Cloning of a Novel Organic Anion Transporter

Friesema

Molecular Endocrinology

2011

345

156

The effects of thyroid hormone (TH) on development and metabolism are exerted at the cellular level. Metabolism and action of TH take place intracellularly, which require transport of the hormone across the plasma membrane. This process is mediated by TH transporter proteins. Many TH transporters have been identified at the molecular level, although a few are classified as specific TH transporters, including monocarboxylate transporter (MCT)8, MCT10, and organic anion-transporting polypeptide 1C1. The importance of TH transporters for physiology has been illustrated dramatically by the causative role of MCT8 mutations in males with psychomotor retardation and abnormal serum TH concentrations. Although Mct8 knockout animals have provided insight in the mechanisms underlying parts of the endocrine phenotype, they lack obvious neurological abnormalities. Thus, the pathogenesis of the neurological abnormalities in males with MCT8 mutations is not fully understood. The prospects of identifying other transporters and transporter-based syndromes promise an exciting future in the TH transporter field.

Section: Organic Anion-transporting Polypeptide 1c1mentioning

confidence: 93%

Minireview: Thyroid Hormone Transporters: The Knowns and the Unknowns

Friesema

Molecular Endocrinology

2011

345

156

Expert Opinion on Therapeutic Targets

“…The BSAT1 mRNA is notable for being expressed abundantly in a rat BBB cDNA library [62]. Northern blot analysis showed the BSAT1 mRNA is highly expressed at the microvasculature in brain, with no detectable expression in rat liver, lung, kidney, or lung [63].…”

Section: Bbb Thyroid Hormone Transportermentioning

confidence: 98%

Blood–brain barrier endogenous transporters as therapeutic targets: a new model for small molecule CNS drug discovery

Pardridge¹

2015

Self Cite

124

“…Accordingly, we detected mRNAs encoding several potential thyroid hormone transporters in cortical neurons. Some of these were formerly known as components of the BBB (e.g., Lat1/Slc7a5 and Oatp-14/ Slco1c1) (Boado et al, 1999;Sugiyama et al, 2003;Chu et al, 2008;Roberts et al, 2008b). Lat1 and Lat2 are BCH-sensitive T 3 transporters and may account for one-half of Mct8-independent T 3 import into neurons.…”

Section: Discussionmentioning

confidence: 99%

“…jneurosci.org as supplemental material). Among these were at lower levels Mct10 (Slc16a10), the closest relative of Mct8, which is also able to efficiently transport T 3 , Oatp-14 (Slco1c1), although it was mostly described in brain microcapillary endothelium (Sugiyama et al, 2003;Chu et al, 2008;Roberts et al, 2008b), and Slco4a1 and Slco4c1, which are less well described. Only Slc7a5 and Slc7a8 (L-type amino acid transporters Lat1 and Lat2, respectively) were expressed at levels comparable with Mct8 in the neurons.…”

Section: Expression Of Thyroid Hormone Transporter Mrna In Mouse Neuronsmentioning

confidence: 99%

Neuronal 3′,3,5-Triiodothyronine (T₃) Uptake and Behavioral Phenotype of Mice Deficient inMct8, the Neuronal T₃Transporter Mutated in Allan–Herndon–Dudley Syndrome

Wirth¹,

Roth²,

et al. 2009

Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the Allan-Herndon-Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3Ј,3,5-triiodothyronine (T 3 ) plasma levels. Mice deficient in Mct8 replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lacking Mct8. Therefore, we subjected Mct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent on Mct8 are in a hypothyroid state, whereas neurons expressing other T 3 transporters become hyperthyroid, if they are exposed directly to the high plasma T 3 . The majority of T 3 uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T 3 transporter classes. mRNAs encoding six T 3 transporters, including L-type amino acid transporters (LATs), were coexpressed with Mct8 in isolated neurons. We then demonstrated Lat2 expression in cultured neurons and throughout murine brain development. In contrast, LAT2 is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype in MCT8-deficient patients, whereas Mct8-deficient mouse neurons are functionally complemented by other transporters, for possibly Lat2.