GLUT1 deficiency and other glucose transporter diseases

Pascual, Juan M.; Wang, Dong; Lecumberri, Beatriz; Yang, Hong; Mao, Xia; Yang, Rongqian; Vivo, Darryl C. De

doi:10.1530/eje.0.1500627

Cited by 131 publications

(103 citation statements)

References 39 publications

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“…Passage across the paracellular pathway disrupts cell-to-cell junction to permit access to the brain. On the other hand, the transcellular pathway is mediated through transporters highly expressed on the luminal side of brain endothelial cells that allow for selective entry of molecules into the brain while maintaining normal brain physiology (12,13). However, multidrug-resistant (MDR) transporters, especially drug efflux transporters, are highly expressed on brain endothelial cells and hinder the effective delivery of drugs into the CNS, including P-glycoprotein (P-gp) and breast cancer-resistant protein 1 (BCRP1/ ABCG2) (3,9,14).…”

Section: Introductionmentioning

confidence: 99%

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

Kim¹,

Bynoe²

2016

Journal of Clinical Investigation

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The blood-brain barrier (BBB) protects the brain from toxic substances within the peripheral circulation. It maintains brain homeostasis and is a hurdle for drug delivery to the CNS to treat neurodegenerative diseases, including Alzheimer's disease and brain tumors. The drug efflux transporter P-glycoprotein (P-gp) is highly expressed on brain endothelial cells and blocks the entry of most drugs delivered to the brain. Here, we show that activation of the A2A adenosine receptor (AR) with an FDA-approved A2A AR agonist (Lexiscan) rapidly and potently decreased P-gp expression and function in a timedependent and reversible manner. We demonstrate that downmodulation of P-gp expression and function coincided with chemotherapeutic drug accumulation in brains of WT mice and in primary mouse and human brain endothelial cells, which serve as in vitro BBB models. Lexiscan also potently downregulated the expression of BCRP1, an efflux transporter that is highly expressed in the CNS vasculature and other tissues. Finally, we determined that multiple pathways, including MMP9 cleavage and ubiquitinylation, mediated P-gp downmodulation. Based on these data, we propose that A2A AR activation on BBB endothelial cells offers a therapeutic window that can be fine-tuned for drug delivery to the brain and has potential as a CNS drug-delivery technology.

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Section: Introductionmentioning

confidence: 99%

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

Kim¹,

Bynoe²

2016

Journal of Clinical Investigation

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“…Owing to their ubiquitous presence and importance, dysfunctions of members of the MFS are related to several diseases, e.g. mutations of the D-glucose transporter (GLUT1, SLC2A1) cause the GLUT1 deficiency syndrome (Pascual et al 2004), GLUT4 (SLC2A4) mutations are associated with non-insulin-dependent diabetes mellitus (Watson & Pessin 2001), and mutations of the monocarboxylate transporter 8 (MCT8) are the underlying cause of a severe X-linked psychomotor retardation, known as the Allan-HerndonDudley syndrome (Friesema et al 2004).…”

Section: Introductionmentioning

confidence: 99%

Modulation of monocarboxylate transporter 8 oligomerization by specific pathogenic mutations

Fischer¹,

Kleinau²,

Müller³

et al. 2015

Journal of Molecular Endocrinology

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The monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS). These membrane-spanning proteins facilitate translocation of a variety of substrates, MCT8 specifically transports iodothyronines. Mutations in MCT8 are the underlying cause of severe X-linked psychomotor retardation. At the molecular level, such mutations led to deficiencies in substrate translocation due to reduced cell-surface expression, impaired substrate binding, or decreased substrate translocation capabilities. However, the causal relationships between genotypes, molecular features of mutated MCT8, and patient characteristics have not yet been comprehensively deciphered. We investigated the relationship between pathogenic mutants of MCT8 and their capacity to form dimers (presumably oligomeric structures) as a potential regulatory parameter of the transport function of MCT8. Fourteen pathogenic variants of MCT8 were investigated in vitro with respect to their capacity to form oligomers. Particular mutations close to the substrate translocation channel (S194F, A224T, L434W, and R445C) were found to inhibit dimerization of MCT8. This finding is in contrast to those for other transporters or transmembrane proteins, in which substitutions predominantly at the outer-surface inhibit oligomerization. Moreover, specific mutations of MCT8 located in transmembrane helix 2 (del230F, V235M, and ins236V) increased the capacity of MCT8 variants to dimerize. We analyzed the localization of MCT8 dimers in a cellular context, demonstrating differences in MCT8 dimer formation and distribution. In summary, our results add a new link between the functions (substrate transport) and protein organization (dimerization) of MCT8, and might be of relevance for other members of the MFS. Finally, the findings are discussed in relationship to functional data combined with structural-mechanistical insights into MCT8.

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“…The SLC superfamily is comprised of transporters from a wide range of functional classes, including neurotransmitter, nutrient, heavy metal, and xenobiotic transporters. Genetic defects in SLC transporters have been associated with a variety of Mendelian diseases, including metabolic disorders such as glucose-galactose malabsorption (Pascual et al 2004) and neurologic disorders such as peripheral neuropathy with agenesis of the corpus callosum (ACCPN) (Howard et al 2002), demonstrating the diverse physiological functions of these proteins.…”

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confidence: 99%

Functional genomics of membrane transporters in human populations

et al. 2005

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Although considerable progress has been made toward characterizing human DNA sequence variation, there remains a deficiency in information on human phenotypic variation at the single-gene level. We systematically analyzed the function of all protein-altering variants of eleven membrane transporters in heterologous expression systems. Coding-region variants were identified by screening DNA from a large sample (n = 247-276) of ethnically diverse subjects. In total, we functionally analyzed 88 protein-altering variants. Fourteen percent of the polymorphic variants (defined as variants with allele frequencies Ն1% in at least one major ethnic group) had no activity or significantly reduced function. Decreased function variants had significantly lower allele frequencies and were more likely to alter evolutionarily conserved amino acid residues. However, variants at evolutionarily conserved positions with approximately normal activity in cellular assays were also at significantly lower allele frequencies, suggesting that some variants with apparently normal activity in biochemical assays may influence occult functions or quantitative degrees of function that are important in human fitness but not measured in these assays. For example, eight (14%) of the 58 variants for which we had measured the transport of at least two substrates showed substrate-specific defects in transport. These variants and the reduced function variants provide plausible candidates for disease susceptibility or variation in clinical drug response.Since the completion of the human genome project, considerable progress has been made in characterizing the nature and degree of human DNA sequence variation (Cargill et al. 1999;Halushka et al. 1999;Patil et al. 2001;Stephens et al. 2001;Leabman et al. 2003). Numerous single nucleotide polymorphisms in all regions of the human genome have been identified, including coding and noncoding regions of genes and large intergenic regions. However, there remains a lack of information connecting genetic polymorphisms to human phenotypic variation. As a consequence, current attempts to predict the functional significance of genetic variants from sequence data alone (from interspecies sequence comparisons or degree of chemical change for amino acid substitutions, as examples) (Sunyaev et al. 2000(Sunyaev et al. , 2001(Sunyaev et al. , 2003Chasman and Adams 2001;Fay et al. 2001;Muller et al. 2001;Henikoff 2001, 2003;Wang and Moult 2001;Ramensky et al. 2002) are lacking in support from empirical data. Furthermore, we have little information on the fraction of natural variants with altered or potentially deleterious function that are harbored in healthy populations. In order to understand variation in normal human physiology and responses to the environment (including, for example, drug-response phenotypes), it is important to understand the range of phenotypic variation that is associated with genetic variation in human populations.Analysis of causal mutations in Mendelian diseases has demonstrated that the majority...

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GLUT1 deficiency and other glucose transporter diseases

Cited by 131 publications

References 39 publications

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

A2A adenosine receptor modulates drug efflux transporter P-glycoprotein at the blood-brain barrier

Modulation of monocarboxylate transporter 8 oligomerization by specific pathogenic mutations

Functional genomics of membrane transporters in human populations

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