S1P1 receptor phosphorylation, internalization, and interaction with Rab proteins: effects of sphingosine 1-phosphate, FTY720-P, phorbol esters, and paroxetine

Author:

Martínez-Morales Juan Carlos1,Romero-Ávila M. Teresa1,Reyes-Cruz Guadalupe2,García-Sáinz J. Adolfo1ORCID

Affiliation:

1. Departamento de Biología Celular y del Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad Universitaria, CP 04510, Ap. Postal 70-248; Mexico City, Mexico

2. Departamento de Biología Celular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional-CINVESTAV, Av Instituto Politécnico Nacional 2508; Col. San Pedro Zacatenco, Mexico City, Mexico

Abstract

Sphingosine 1-phosphate (S1P) and FTY720-phosphate (FTYp) increased intracellular calcium in cells expressing S1P1 mCherry-tagged receptors; the synthetic agonist was considerably less potent. Activation of protein kinase C by phorbol myristate acetate (PMA) blocked these effects. The three agents induced receptor phosphorylation and internalization, with the action of FTYp being more intense. S1P1 receptor–Rab protein (GFP-tagged) interaction was studied using FRET. The three agents were able to induce S1P1 receptor–Rab5 interaction, although with different time courses. S1P1 receptor–Rab9 interaction was mainly increased by the phorbol ester, whereas S1P1 receptor–Rab7 interaction was only increased by FTYp and after a 30-min incubation. These actions were not observed using dominant negative (GDP-bound) Rab protein mutants. The data suggested that the three agents induce interaction with early endosomes, but that the natural agonist induced rapid receptor recycling, whereas activation of protein kinase C favored interaction with late endosome and slow recycling and FTYp triggered receptor interaction with vesicles associated with proteasomal/lysosomal degradation. The ability of bisindolylmaleimide I and paroxetine to block some of these actions suggested the activation of protein kinase C was associated mainly with the action of PMA, whereas G protein-coupled receptor kinase (GRK) 2 (GRK2) was involved in the action of the three agents.

Publisher

Portland Press Ltd.

Subject

Cell Biology,Molecular Biology,Biochemistry,Biophysics

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