Vitamin A Transport Mechanism of the Multitransmembrane Cell-Surface Receptor STRA6.

Vitamin A has biological functions as diverse as sensing light for vision, regulating stem cell differentiation, maintaining epithelial integrity, promoting immune competency, regulating learning and memory, and acting as a key developmental morphogen. Vitamin A derivatives have also been used in treating human diseases. If vitamin A is considered a drug that everyone needs to take to survive, evolution has come up with a natural drug delivery system that combines sustained release with precise and controlled delivery to the cells or tissues that depend on it. This "drug delivery system" is mediated by plasma retinol binding protein (RBP), the principle and specific vitamin A carrier protein in the blood, and STRA6, the cell-surface receptor for RBP that mediates cellular vitamin A uptake. The mechanism by which the RBP receptor absorbs vitamin A from the blood is distinct from other known cellular uptake mechanisms. This review summarizes recent progress in elucidating the fundamental molecular mechanism mediated by the RBP receptor and multiple newly discovered catalytic activities of this receptor, and compares this transport system with retinoid transport independent of RBP/STRA6. How to target this new type of transmembrane receptor using small molecules in treating diseases is also discussed

Identification of PLXDC1 and PLXDC2 as the transmembrane receptors for the multifunctional factor PEDF.

Pigment Epithelium Derived Factor (PEDF) is a secreted factor that has broad biological activities. It was first identified as a neurotrophic factor and later as the most potent natural antiangiogenic factor, a stem cell niche factor, and an inhibitor of cancer cell growth. Numerous animal models demonstrated its therapeutic value in treating blinding diseases and diverse cancer types. A long-standing challenge is to reveal how PEDF acts on its target cells and the identities of the cell-surface receptors responsible for its activities. Here we report the identification of transmembrane proteins PLXDC1 and PLXDC2 as cell-surface receptors for PEDF. Using distinct cellular models, we demonstrate their cell type-specific receptor activities through loss of function and gain of function studies. Our experiments suggest that PEDF receptors form homooligomers under basal conditions, and PEDF dissociates the homooligomer to activate the receptors. Mutations in the intracellular domain can have profound effects on receptor activities

Executive function and ADHD

Objective. To examine the profile of executive function (EF) performance in children diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) as function of their subtypes and comorbid disorders. Methods. Two hundred and eighteen, 6-12 year old children clinically diagnosed with ADHD were characterised according to their clinical profile. Various EF domains were assessed while children were not on medication. General cognitive performance was assessed using Wechsler Intelligence Scale for Children. Results. 54.1% of children were diagnosed with combined subtype, 34.9% with inattentive subtype and 11% with hyperactive subtype. Significant age difference was found in ADHD subtype distribution and significant age and IQ difference was found in EF performance. After controlling for age and IQ no association was found between EF and ADHD subtypes or EF and comorbid disorders. Conclusion. These results indicate that age and IQ play an important role in cognitive task performance

Executive function in attention deficit hyperactivity disorder (ADHD):Examining the role of subtypes and comorbid disorders

The relationship between Attention Deficit Hyperactivity Disorder (ADHD) and Executive Function (EF) continues to be at the forefront of research. An improved understanding of this relationship will advance the assessment and treatment of individuals with ADHD. The purpose of this dissertation is to examine how the clinical presentation of ADHD relates to performance on EF tasks in children age 6 to 12, diagnosed with ADHD. The first manuscript examines the relationship between ADHD symptoms and EF performance. Three hundred and sixty three children were included in the study. Children performed a battery of neuropsychological tests, commonly used to assess EF. The three DSM-IV ADHD subtypes and the Sluggish Cognitive Tempo (SCT) subtype were examined. The results indicate that children’s performance differed depending on the DSM-IV subtype diagnosis and on SCT. However, when age was controlled, the results were no longer significant. This finding suggests that age plays a significant role in children’s performance on EF tasks. The second manuscript further examines EF, but takes into consideration the presence of comorbid disorders. This study included 355 children, ages 6-12. Children completed a neurocognitive battery, which included measures of working memory, set-shifting, planning, and attention. The comorbid disorders examined were Oppositional Defiant Disorder (ODD), Conduct Disorder (CD) and anxiety disorders. Significant differences were found between children with anxiety disorders and without anxiety disorders on measures of attention and working memory. A significant difference was found between children with CD and without CD on set-shifting measure, and a significant sex by CD interaction was observed on this measure. The results stress the importance of considering comorbid disorders when assessing and treating children with ADHD.La relation entre le trouble du déficit de l'attention avec hyperactivité (TDAH) et les fonctions exécutives demeure au centre des recherches actuelles. Une meilleure compréhension de cette relation influera sur l’évaluation et le traitement des personnes présentant un TDAH. L’objectif de cette étude est d’examiner le lien entre la présentation clinique du TDAH et la performance de tâches faisant appel aux fonctions exécutives d’enfants de 6 à 12 ans présentant un TDAH. La premier étude examine la relation entre les symptômes du TDAH et les fonctions exécutives. Trois cent soixante-trois enfants ont été inclus dans cette étude. Les enfants ont fait l’objet d’une série de tests neuropsychologiques couramment utilisés dans l’évaluation des fonctions exécutives. Les trois sous-types de TDAH du DSM-IV et le sous-type de rythme cognitif lent (RCL) ont été examinés. Les résultats indiquent que les performances des enfants différaient en fonction du diagnostic du sous-type DSM-IV et RCL. Cependant, lorsque l’âge était contrôlé, les résultats cessaient d’être significatifs. Ces résultats suggèrent que l’âge joue un rôle important dans la performance de tâches faisant appel aux fonctions exécutives chez les enfants. La deuxième étude pousse l’examen des fonctions exécutives, mais en tenant compte de la présence de troubles comorbides. Dans cette étude, trois cent cinquante-cinq enfants de 6 à 12 ans ont été inclus. Les enfants ont fait l’objet d’une série de tests neurocognitifs incluant des mesures de la mémoire de travail, de la souplesse cognitive, de la planification et de l’attention. Les troubles comorbides examinés étaient le trouble oppositionnel avec provocation (TOP), le trouble des conduites et les troubles anxieux. D’importantes différences ont été relevées entre les enfants présentant ou non des troubles anxieux dans le cadre des mesures de l’attention et de la mémoire de travail. Une différence importante a été relevée dans le cadre des mesures de souplesse cognitive entre les enfants ayant un trouble des conduites; de plus, une interaction significative a également été notée entre le sexe et le trouble des conduites pour cette mesure. Ces résultats soulignent l’importance de tenir compte des troubles comorbides lors de l’évaluation et du traitement d’enfants présentant un TDAH

Vitamin A transport and the transmembrane pore in the cell-surface receptor for plasma retinol binding protein.

Vitamin A and its derivatives (retinoids) play diverse and crucial functions from embryogenesis to adulthood and are used as therapeutic agents in human medicine for eye and skin diseases, infections and cancer. Plasma retinol binding protein (RBP) is the principal and specific vitamin A carrier in the blood and binds vitamin A at 1:1 ratio. STRA6 is the high-affinity membrane receptor for RBP and mediates cellular vitamin A uptake. STRA6 null mice have severely depleted vitamin A reserves for vision and consequently have vision loss, even under vitamin A sufficient conditions. STRA6 null humans have a wide range of severe pathological phenotypes in many organs including the eye, brain, heart and lung. Known membrane transport mechanisms involve transmembrane pores that regulate the transport of the substrate (e.g., the gating of ion channels). STRA6 represents a new type of membrane receptor. How this receptor interacts with its transport substrate vitamin A and the functions of its nine transmembrane domains are still completely unknown. These questions are critical to understanding the molecular basis of STRA6's activities and its regulation. We employ acute chemical modification to introduce chemical side chains to STRA6 in a site-specific manner. We found that modifications with specific chemicals at specific positions in or near the transmembrane domains of this receptor can almost completely suppress its vitamin A transport activity. These experiments provide the first evidence for the existence of a transmembrane pore, analogous to the pore of ion channels, for this new type of cell-surface receptor

Attention and executive function in children diagnosed with attention deficit hyperactivity disorder and comorbid disorders

OBJECTIVE: The goal of this study was to examine the relationship between comorbid disorders and executive function (EF) in children diagnosed with Attention Deficit/Hyperactivity Disorder (ADHD). METHODS: Three hundred and fifty-five, 6–12 year old children clinically diagnosed with ADHD were included in the study. Comorbid anxiety disorders, Oppositional Defiant Disorder (ODD) and Conduct Disorder (CD) were examined. The EF domains were assessed using the Conners’ Continuous Performance Test (CPT), Wisconsin Card Sorting Test (WCST), Tower of London (ToL), Finger Windows (FW) and Self Ordered Pointing Test (SOPT). RESULTS: The findings indicate that children with comorbid anxiety disorders performed worse in domains measured by CPT and prior to controlling for age and sex, by FW. However, once sex was controlled for the results for FW were no longer significant. Children with CD obtained lower scores on WCST. Furthermore, a significant sex by CD interaction was observed. CONCLUSION: These results indicate that comorbid disorders should be carefully examined as they play a significant role in EF performance and subsequently in day-to-day functioning of children with ADHD

Schematic diagrams of the locations of key positions in STRA6 whose acute modifications block vitamin A transport by STRA6.

<p><b>A.</b> Helical wheel presentations of residues L293 to L303 and residues F379 to H389. Residues whose modification by MTSEA-biotin impedes vitamin A transport by STRA6 are labeled in light red. These key residues are located on the same side of the helix. <b>B.</b> Locations of the key residues in the transmembrane topology model of STRA6. Residues whose acute modification impedes vitamin A transport by STRA6 are represented as red circles.</p

Comparison and quantitation of the acute suppression by MTSEA-biotin for all STRA6 cysteine mutants produced and analyzed in the study.

<p>Suppression of the wild-type control is defined as 1. <b>A.</b> Mutations in or near the sixth transmembrane helix. <b>B.</b> Mutations in or near the seventh transmembrane helix. Statistical analysis is shown as *** (<i>p</i><0.001), ** (<i>p</i><0.01), or * (<i>p</i><0.05). Mutants not labeled were not statistically different from the wild-type control.</p

Scanning the sixth transmembrane helix of STRA6 for positions that enhance the sensitivity of STRA6 to MTSEA-biotin modification.

<p>Thirty two residues in or near the sixth transmembrane domain of STRA6 were each changed to cysteine. Each mutant was tested for STRA6-catalyzed retinol release from holo-RBP. Grey traces, no modification. Red traces, MTSEA-biotin modification. All experiments were done in triplicate.</p

Real-time analysis of STRA6-catalyzed transport of retinol from holo-RBP to EGFP-CRBP-I.

<p><b>A.</b> Schematic diagram of the use of retinol-EGFP FRET to monitor the transport of retinol from holo-RBP to EGFP-CRBP-I. FRET is indicated by an orange arrow. <b>B and C.</b> Effects of MTSEA-biotin treatment on the retinol transport by STRA6 WT and STRA6-S385C, respectively. Grey traces, no treatment. Green traces, MTSEA-biotin treatment. Control membrane without STRA6 was used as the negative control in B (open circles). <b>D.</b> Comparison of the effects of MTSEA-biotin on STRA6-WT and STRA6-S385C at 60 min. The signal of the untreated reaction for STRA6-WT is defined as 1. Grey bars, no treatment. Green bars, MTSEA-biotin treatment. <b>E.</b> Comparison of effects of MTSEH, MTSBS, MTSPT and MTSEA-biotin of retinol transport activity of STRA6-S385C. <b>F.</b> Quantitation of the FRET signals from experiments in E. The signal of the untreated reaction is defined as 1.</p