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Receptors and Transporters

開催日 2014/9/11
時間 16:00 - 17:00
会場 Poster / Exhibition(Event Hall B)

細胞内におけるドパミン D2L 受容体の新しい活性化機構
Novel activation mechanism of intracellular dopamine D2L receptor

  • P1-028
  • 塩田 倫史 / Norifumi Shioda:1 笹原 正清 / Masakiyo Sasahara:2 森 寿 / Hisashi Mori:3 福永 浩司 / Kohji Fukunaga:1 
  • 1:東北大学 / Dept. Pharmacol., Grad. Sch. Pharmaceu.Sci., Tohoku Univ. 2:富山大・医・病態病理学 / Dept. Pathology, Grad. Sch. Med. and Pharm. Sci., Univ of Toyama 3:富山大・医・分子神経科学 / Dept Mol Neurosci, Grad. Sch. Med. and Pharm. Sci., Univ of Toyama 

The dopamine D2 receptor (D2R) is target for antipsychotic drugs and its abnormality is associated with several neuropsychiatric disorders. The D2R has two alternatively spliced isoforms, termed D2LR and D2SR. D2LR, but not D2SR transactivates receptor tyrosine kinase pathways, including PDGFRbeta. We previously demonstrated that D2SR is predominantly expressed in the plasma membrane, whereas D2LR is mostly retained in the Golgi apparatus. However, the molecular mechanisms and physiological roles of the intracellular D2LR remain unclear. When D2LR or D2SR is transfected with PDGFRbeta in HEK293T cells, D2SR stimulation with dopamine produced a transient increase in ERK phosphorylation, whereas D2LR stimulation with dopamine caused significant and persistent ERK activation. The persistent kinase activation was completely blocked by pertussis-toxin, PDGFR inhibitor tyrphostin A9 and dynamin inhibitor Dynasore, suggesting the dopamine-induced receptor internalization is involved in the D2LR signaling. In addition, we analyzed the interactions of D2LR with Galpha-i isoforms using BRET method. Dopamine caused a significant BRET change in cells expressing D2LR-RLuc8 with Galpha-i3-mVenus compared with the effect of Galpha-i1 and Galpha-i2. Galpha-i3 was localized in both plasma membrane and Golgi apparatus, in where it colocalized with D2LR. Taken together, the intracellular dopamine D2LR is predominantly associated with Galpha-i3, and the dopamine-induced internalization of D2LR leads to making D2LR-PDGFRbeta complex in the Golgi apparatus, thereby eliciting persist activation of ERK pathway.

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