Functional expression of dopamine D2 receptor is regulated by tetraspanin 7–mediated postendocytic trafficking

• Published in: The FASEB journal 2017-06, Vol.31 (6), p.2301-2313
• Main Authors: Lee, Seol‐Ae, Suh, Yeongjun, Lee, Saebom, Jeong, Jaehoon, Kim, Soo Jeong, Kim, So Jung, Park, Sang Ki
• Format: Article
• Language: English
• Subjects: Animals; Brain; Cell Line; cell surface trafficking; Compartments; Deregulation; Dopamine; Dopamine D2 receptors; dopaminergic signaling; Endocytosis; Endosomes; Gene Expression Regulation - physiology; Humans; Internalization; Localization; Locomotion; Mental disorders; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Protein Isoforms; Protein Transport; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; Reinforcement; Signal Transduction; Signaling; Tetraspanins - genetics; Tetraspanins - metabolism; Tissues
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201600755RR

ABSTRACT The dopaminergic system plays an essential role in various functions of the brain, including locomotion, memory, and reward, and the deregulation of dopaminergic signaling as a result of altered functionality of dopamine D2 receptor (DRD2) is implicated in multiple neurologic and psychiatric disorders. Tetraspanin‐7 (TSPAN7) is expressed to variable degrees in different tissues, with the highest level in the brain, and multiple mutations in TSPAN7 have been implicated in intellectual disability. Here, we tested the hypothesis that TSPAN7 may be a binding partner of DRD2 that is involved in the regulation of its functional activity. Our results showed that TSPAN7 was associated with DRD2 and reduced its surface expression by enhancing DRD2 internalization. Immunocytochemical analysis revealed that TSPAN7 that resides in the plasma membrane and early and late endosomes promoted internalization of DRD2 and its localization to endosomal compartments of the endocytic pathway. Furthermore, we observed that TSPAN7 deficiency increased surface localization of DRD2 concurrent with the decrease of its endocytosis, regardless of dopamine treatment. Finally, TSPAN7 negatively affects DRD2‐mediated signaling. These results disclosed a previously uncharacterized role of TSPAN7 in the regulation of the expression and functional activity of DRD2 by postendocytic trafficking.—Lee, S.‐A., Suh, Y., Lee, S., Jeong, J., Kim, S. J., Kim, S. J., Park, S. K. Functional expression of dopamine D2 receptor is regulated by tetraspanin 7–mediated postendocytic trafficking. FASEB J. 31, 2301–2313 (2017). www.fasebj.org