Organic anion transporting polypeptide 3A1 (OATP3A1, encoded by the SLCO3A1 gene)
is a prostaglandin, oligopeptide, and steroid/thyroid hormone transporter with wide
tissue distribution, expressed, e.g., in the human brain and testis. Although the
physiological importance of OATP3A1 has not yet been clarified, based on its expression
pattern, substrate recognition, and evolutionary conservation, OATP3A1 is a potential
pharmacological target. Previously, two isoforms of OATP3A1, termed as V1 and V2,
have been characterized. Here, we describe the cloning and functional characterization
of a third isoform, OATP3A1_V3. The mRNA of isoform V3 is formed by alternative splicing
and results in an OATP3A1 protein with an altered C-terminus compared to isoforms
V1 and V2. Based on quantitative PCR, we demonstrate the widespread expression of
SLCO3A1_V3 mRNA in human organs, with the highest expression in the brain and testis.
By generation of an isoform V3-specific antibody and immunostaining, we show that
the encoded protein is expressed in the human choroid plexus, neurons, and both germ
and Sertoli cells of the testis. Moreover, we demonstrate that in contrast to isoform
V1, OATP3A1_V3 localizes to the apical membrane of polarized MDCKII cells. Using HEK-293
cells engineered to overexpress OATP3A1_V3, we verify the protein's functionality
and identify dehydroepiandrosterone sulfate as a novel OATP3A1 substrate. Based on
their distinct expression patterns but overlapping functions, OATP3A1 isoforms may
contribute to transcellular (neuro)steroid transport in the central nervous system.
