Neurosteroid Transport in the Brain: Role of ABC and SLC Transporters

Abstract

Neurosteroids, comprising pregnane, androstane, and sulfated steroids can alter neuronal excitability through interaction with ligand-gated ion channels and other receptors and have therefore a therapeutic potential in several brain disorders. They can be formed in brain cells or are synthesized by an endocrine gland and reach the brain by penetrating the blood–brain barrier (BBB). Especially sulfated steroids such as pregnenolone sulfate (PregS) and dehydroepiandrosterone sulfate (DHEAS) depend on transporter proteins to cross membranes. In this review, we discuss the involvement of ATP-binding cassette (ABC)- and solute carrier (SLC)-type membrane proteins in the transport of these compounds at the BBB and in the choroid plexus (CP), but also in the secretion from neurons and glial cells. Among the ABC transporters, especially BCRP (ABCG2) and several MRP/ABCC subfamily members (MRP1, MRP4, MRP8) are expressed in the brain and known to efflux conjugated steroids. Furthermore, several SLC transporters have been shown to mediate cellular uptake of steroid sulfates. These include members of the OATP/SLCO subfamily, namely OATP1A2 and OATP2B1, as well as OAT3 (SLC22A3), which have been reported to be expressed at the BBB, in the CP and in part in neurons. Furthermore, a role of the organic solute transporter OSTα-OSTβ (SLC51A/B) in brain DHEAS/PregS homeostasis has been proposed. This transporter was reported to be localized especially in steroidogenic cells of the cerebellum and hippocampus. To date, the impact of transporters on neurosteroid homeostasis is still poorly understood. Further insights are desirable also with regard to the therapeutic potential of these compounds.

A novel fluorescence‐based functional assay for human OATP1A2 and OATP1C1 identifies interaction between third‐generation P‐gp inhibitors and OATP1A2

“…Therefore, OATP1A2 may be exploited for increased uptake of CNS‐targeted drugs, enabling the successful treatment of various CNS diseases. On the other hand, since OATP1A2 also transports the neurosteroid DHEAS, modification of its function may influence DHEAS levels in the brain and hence influence neuron excitability . Finally, CNS toxicity of drugs may also be related to OATP1A2‐mediated transport, as documented in the case of several OATP1A2 substrates, including methotrexate, levofloxacin, and microcystins .…”

Drug Transport at the Brain and Endothelial Dysfunction in Preeclampsia: Implications and Perspectives

“…In human BECs, BCRP is expressed at higher levels than P-GP ( Shawahna et al, 2011 ; Uchida et al, 2011 ), but its overall contribution to the transport of substrates is less well understood than P-GP. As well as transporting drug substrates, BCRP also participates in transport of hormones (and conjugated metabolites) ( Grube et al, 2018 ) and urate, a product of purine metabolism whose accumulation causes gout ( Woodward et al, 2009 ; Fujita and Ichida, 2018 ).…”

Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: A case series

“…Patient 2 also carried a predicted moderate‐risk variant (rs939885) in SLC51A . SLC51A is an essential component of the Ost‐alpha/Ost‐beta complex, a heterodimer that acts as an organic solute transporter of the sulfated neurosteroids pregnenolone sulfate (PREGS) and dehydroepiandrosterone sulfate (DHEAS) (Grube et al, ). Ost‐alpha deficient mice exhibited changes in serum DHEA and DHEAS levels, and in tissue distribution of administered DHEAS (Fang et al, ).…”

“…Haploinsufficiency of FBXO45 (OMIM 609,112), DLG1 (OMIM 601,014), and PAK2 (OMIM 605,022) have been proposed as causative of the neuropsychiatric manifestations because they play putative roles in synaptic transmission (Carroll et al, ). Genes with impact on cilia function ( CEP19 (OMIM 615,586), TCTEX1D2 (OMIM 617,353) (Marley & von Zastrow, ; Youn & Han, ), neurosteroid transport ( SLC51A (OMIM 612,084)) (Cai, Cao, Zhou, & Yao, ; Grube, Hagen, & Jedlitschky, ; Tuem & Atey, ), iron homeostasis, and synaptic plasticity ( TFRC (OMIM 190,010)) (Liu et al, ; Matak et al, ) are also of great interest regarding neuropsychiatric diversity. In addition to the possible effects of haploinsufficiency, another hypothesis lies in the fact that genetic variation within the nondeleted 3q29 allele could influence the neuropsychiatric phenotype.…”