Characterization of agonist-dependent somatostatin receptor subtype 2 trafficking in neuroendocrine cells
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ORIGINAL ARTICLE
Characterization of agonist-dependent somatostatin receptor subtype 2 trafficking in neuroendocrine cells Walaa Alshafie1 Yingzhou Edward Pan1,2 Hans-Jürgen Kreienkamp2 Thomas Stroh ●
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Received: 21 January 2020 / Accepted: 23 April 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Background Somatostatin (SOM) receptor subtype 2 (SSTR2) is the major receptor subtype mediating SOM effects throughout the neuraxis. We previously demonstrated that the non-selective agonist [D-Trp8]-SOM induces intracellular sequestration of SSTR2, whereas this receptor is maintained at the cell surface after treatment with the SSTR2-selective agonist L-779,976 in cells co-expressing SSTR2 and SSTR5. Methods and results In this study, we knocked-out SSTR5 in AtT20 cells endogenously expressing both SSTR2 and SSTR5 and used immuno-labeling and confocal microscopy to investigate the effect of SSTR5 on regulation of SSTR2 trafficking. Our results indicate that unlike [D-Trp8]-SOM-induced intracellular sequestration, L-779,976 stimulation results in the maintenance of SSTR2 at the cell surface regardless of whether SSTR5 is present or not. We then examined the trafficking pathways of SSTR2 upon stimulation by either agonist. We found that both [D-Trp8]-SOM and L-779,976 induce SSTR2 internalization via transferrin-positive vesicles. However, SSTR2 internalized upon L-779,976 treatment undergoes rapid recycling to the plasma membrane, whereas receptors internalized by [D-Trp8]-SOM recycle slowly after washout of the agonist. Furthermore, [D-Trp8]-SOM stimulation induces degradation of a fraction of internalized SSTR2 whereas L-779,976-dependent, rapid SSTR2 recycling appears to protect internalized SSTR2 from degradation. In addition, Octreotide which has preferential SSTR2 affinity, induced differential effects on both SSTR2 trafficking and degradation. Conclusion Our results indicate that the biased agonistic property of L-779,976 protects against SSTR2 surface depletion by rapidly initiating SSTR2 recycling while SSTR5 does not regulate L-779-976-dependent SSTR2 trafficking. Keywords Somatostatin SSTR2 SSTR5 Intracellular trafficking Recycling ●
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Introduction Somatostatin (SOM) is a neuropeptide that has a wide distribution not only in the central nervous system but throughout the body [1]. It was first isolated and
Supplementary information The online version of this article (https:// doi.org/10.1007/s12020-020-02329-x) contains supplementary material, which is available to authorized users. * Walaa Alshafie walaa.alshafi[email protected] * Thomas Stroh [email protected] 1
Department of Neurology and Neurosurgery, McGill University, and the Montreal Neurological Institute, Montreal, QC, Canada
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Institute for Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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characterized based on its potent inhibitory action on the secretion of pituitary hormones by endocrine cells from the anterior pituitary gland [2]. Its a
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