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This version published online on October 23, 2003
Endocrinology, doi:10.1210/en.2003-0974
A more recent version of this article appeared on February 1, 2004
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Submitted on July 30, 2003
Accepted on October 14, 2003

Desensitization And Endocytosis Mechanisms Of Ghrelin-Activated Growth Hormone Secretagogue Receptor 1a

Jesus P Camiña1, Marcos C Carreira1, Said El Messari1, Catherine Llorens-Cortes1, Roy G Smith1, and Felipe F Casanueva1*

1 Department of Medicine. Research Area, Molecular Endocrinology Laboratory. Complejo Hospitalario Universitario de Santiago (CHUS) and University of Santiago de Compostela, Spain. Institut National de la Sante et de la Recherche Medicale, Unite 36, College de France, Chaire de Medecine Experimentale, Paris, France. Huffington Center on Aging and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, USA.

* To whom correspondence should be addressed. E-mail: endocrine{at}usc.es.

In this work, a sequential analysis of pathways involved in the regulation of growth hormone secretagogue receptor subtype 1a (GHSR-1a) signaling has been undertaken to characterize the process of rapid desensitization that is observed following ghrelin binding. This process was evaluated by studying the binding of [125I]-ghrelin, measurement of intracellular calcium mobilization and confocal microscopy. The results indicate that GHSR-1a is mainly localized at the plasma membrane under unstimulated conditions and rapidly desensitizes after stimulation. The agonist-dependent desensitization is not mediated by protein kinase C (PKC) since phorbol ester, PMA, failed to block the ghrelin-induced calcium response. The ghrelin/GHSR-1a complex progressively disappears from the plasma membrane after 20 min exposure to ghrelin and accumulates in the perinuclear region after 60 min. Colocalization of the internalized GHSR-1a with the early endosome marker (EEA1) after 20 min exposure to ghrelin suggests that endocytosis occurs via clathrin coated pits, which is consistent with the lack of internalization of this receptor observed after potassium depletion. At different to other G protein-coupled receptors, GHSR-1a showed slow recycling. Surface binding slowly recovered after agonist treatment and returned to control levels within 360 min. Furthermore, inhibition of vacuolar H+-ATPases prevented recycling of the receptor, suggesting that the non-dissociation of the ligand/receptor complex is responsible for this effect. The GHSR-1a internalization may explain the characteristic physiological responses mediated by this receptor.
Key words: ghrelin • growth hormone secretagogues • growth hormone secretagogue receptor-1a




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