Mfsd2a-based pharmacological strategies for drug delivery across the blood–brain barrier

Wang, Jing-Zhang; Xiao, Ningchuan; Zhang, Yingzhou; Zhao, Chao; Guo, Xinhua; Lu, L.

doi:10.1016/j.phrs.2015.12.024

Cited by 37 publications

(24 citation statements)

References 108 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dominant hereditary spastic paraplegia (SPG6), amyotrophic lateral sclerosis (ALS); Congenital ichthyosis (Blauw et al, 2012;Dahlqvist et al, 2007;Lefevre et al, 2004;Rainier et al, 2003) SLC58 Physiologically, might play a role in blood-brain barrier (BBB) drug delivery and is the syncytin-2 receptor (Alakbarzade et al, 2015;Ben-Zvi et al, 2014;Toufaily et al, 2013;Wang et al, 2016 (Nurnberg et al, 2001;Reichenberger et al, 2001;Tsui et al, 2005;Williams et al, 2002) SLC63…”

Section: Sideroflexinsmentioning

confidence: 99%

Structural biology of solute carrier (SLC) membrane transport proteins

Bai

Moraes

Reithmeier

2017

Molecular Membrane Biology

142

101

View full text Add to dashboard Cite

The human solute carriers (SLCs) comprise over 400 different transporters, organized into 65 families (http://slc.bioparadigms.org/) based on their sequence homology and transport function. SLCs are responsible for transporting extraordinarily diverse solutes across biological membranes, including inorganic ions, amino acids, lipids, sugars, neurotransmitters and drugs. Most of these membrane proteins function as coupled symporters (co-transporters) utilizing downhill ion (H þ or Na þ) gradients as the driving force for the transport of substrate against its concentration gradient into cells. Other members work as antiporters (exchangers) that typically contain a single substrate-binding site with an alternating access mode of transport, while a few members exhibit channel-like properties. Dysfunction of SLCs is correlated with numerous human diseases and therefore they are potential therapeutic drug targets. In this review, we identified all of the SLC crystal structures that have been determined, most of which are from prokaryotic species. We further sorted all the SLC structures into four main groups with different protein folds and further discuss the well-characterized MFS (major facilitator superfamily) and LeuT (leucine transporter) folds. This review provides a systematic analysis of the structure, molecular basis of substrate recognition and mechanism of action in different SLC family members.

show abstract

Section: Sideroflexinsmentioning

confidence: 99%

Structural biology of solute carrier (SLC) membrane transport proteins

Bai

Moraes

Reithmeier

2017

Molecular Membrane Biology

142

101

View full text Add to dashboard Cite

show abstract

“…If we instead consider AMTF8, both MFSD2A and MFSD2B are located to the endoplasmic reticulum [ 37 ], while MFSD2A is also detected in the plasmalemma [ 42 ]. As they are nearly 40% identical, it is likely that they share a substrate and mechanism, and as MFSD2B transports lipids in a sodium-dependent manner [ 43 ], it is possible that MFSD2B does so as well.…”

Section: Discussionmentioning

confidence: 99%

Characteristics of 29 novel atypical solute carriers of major facilitator superfamily type: evolutionary conservation, predicted structure and neuronal co-expression

et al. 2017

View full text Add to dashboard Cite

Solute carriers (SLCs) are vital as they are responsible for a major part of the molecular transport over lipid bilayers. At present, there are 430 identified SLCs, of which 28 are called atypical SLCs of major facilitator superfamily (MFS) type. These are MFSD1, 2A, 2B, 3, 4A, 4B, 5, 6, 6 L, 7, 8, 9, 10, 11, 12, 13A, 14A and 14B; SV2A, SV2B and SV2C; SVOP and SVOPL; SPNS1, SPNS2 and SPNS3; and UNC93A and UNC93B1. We studied their fundamental properties, and we also included CLN3, an atypical SLC not yet belonging to any protein family (Pfam) clan, because its involvement in the same neuronal degenerative disorders as MFSD8. With phylogenetic analyses and bioinformatic sequence comparisons, the proteins were divided into 15 families, denoted atypical MFS transporter families (AMTF1-15). Hidden Markov models were used to identify orthologues from human to Drosophila melanogaster and Caenorhabditis elegans. Topology predictions revealed 12 transmembrane segments (for all except CLN3), corresponding to the common MFS structure. With single-cell RNA sequencing and in situ proximity ligation assay on brain cells, co-expressions of several atypical SLCs were identified. Finally, the transcription levels of all genes were analysed in the hypothalamic N25/2 cell line after complete amino acid starvation, showing altered expression levels for several atypical SLCs.

show abstract

“…Transient opening of the BBB via concomitant administration of an Mfsd2a inhibitor and the therapeutic drug is a possible way of drug delivery into the CNS (Wang et al, ). However, there are no currently available and proven inhibitors of Mfsd2a.…”

Section: Roles Of Mfsd2a In Physiological and Pathological Conditionsmentioning

confidence: 99%

“…Since its discovery, various in vivo and in vitro studies have revealed the involvement of Mfsd2a in different systems of the mammalian body (Table ). One of the exciting breakthroughs has been the identification of the role of Mfsd2a in the mediation of the blood–brain barrier (BBB) permeability by selective transportation of the lysophosphatidylcholine (LPC)‐binded fatty acids (Nguyen et al, ), which brought Mfsd2a forward as a potential therapeutic target for drug delivery into the central nervous system (CNS) (Wang et al, ). Additionally, the role of Mfsd2a in tumor development and progression, and maintenance of the functions of placenta and blood–retina barrier (BRB) as well as its contributions to inflammation, organ damage, and regeneration in various systems are noteworthy (Tables and ).…”

Section: Introductionmentioning

confidence: 99%

Insights into major facilitator superfamily domain‐containing protein‐2a (Mfsd2a) in physiology and pathophysiology. What do we know so far?

Ocak

Sherchan

et al. 2018

J of Neuroscience Research

View full text Add to dashboard Cite

Major facilitator superfamily domain-containing protein-2a (Mfsd2a) which was considered as an orphan transporter has recently gained attention for its regulatory role in the maintenance of proper functioning of the blood-brain barrier. Besides the major role of Mfsd2a in maintaining the barrier function, increasing evidence has emerged with regard to the contributions of Mfsd2a to various biological processes such as transport, cell fusion, cell cycle, inflammation and regeneration, managing tumor growth, functioning of other organs with barrier functions or responses to injury. The purpose of this article is to review the different roles of Mfsd2a and its involvement in the physiological and pathophysiological processes primarily in the central nervous system and throughout the mammalian body under the lights of the current literature.

show abstract

Mfsd2a-based pharmacological strategies for drug delivery across the blood–brain barrier

Cited by 37 publications

References 108 publications

Structural biology of solute carrier (SLC) membrane transport proteins

Structural biology of solute carrier (SLC) membrane transport proteins

Characteristics of 29 novel atypical solute carriers of major facilitator superfamily type: evolutionary conservation, predicted structure and neuronal co-expression

Insights into major facilitator superfamily domain‐containing protein‐2a (Mfsd2a) in physiology and pathophysiology. What do we know so far?

Contact Info

Product

Resources

About