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Annexin 1-Dependent Actions of Glucocorticoids in the Anterior Pituitary Gland: Roles of the N-Terminal Domain and Protein Kinase C

Department of Neuroendocrinology (C.J., P.C., E.S., J.B.), Division of Neuroscience and Psychological Medicine, Faculty of Medicine, Imperial College of Science Technology and Medicine, Hammersmith Hospital Campus, London W12 ONN, United Kingdom; Department of Human Anatomy and Genetics (J.M., H.C.), The University of Oxford, Oxford OX1 3QX, United Kingdom; and Department of Biochemical Pharmacology (R.F.), The William Harvey Research Institute, St Bartholomew’s and the Royal London School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom

Address all correspondence and requests for reprints to: Professor Julia Buckingham, Department of Neuroendocrinology, Faculty of Medicine, Imperial College of Science Technology and Medicine, Commonwealth Building, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom. E-mail: . j.buckingham{at}ic.ac.uk

Annexin 1 (ANXA1) is an important mediator of glucocorticoid action in the neuroendocrine system. As the activity of this protein in other systems is modulated by phosphorylation of its N-terminal domain, we have explored the significance of this domain and its phosphorylation status to ANXA1 actions within the pituitary gland, using an established in vitro preparation. Two N-terminal peptides, ANXA1_Ac2–26 and ANXA1_Ac1–50, inhibited forskolin-evoked ACTH and prolactin release; however, they lacked the potency and full efficacy of the parent molecule (ANXA1_1–346), whereas other shorter N-terminal sequences were without effect. A chimeric protein comprising ANXA1_1–44 and the C-terminal core of ANXA5 (ANXA5_20–320) also produced a partial inhibition of peptide release. Protein kinase C (PKC) blockade (PKC_19–36) abolished the inhibitory effects of dexamethasone on forskolin-evoked peptide release and attenuated the antisecretory actions of ANXA1_Ac2–26. ANXA5, which sequesters PKC in other systems, produced similar effects. PKC_19–36 also blocked the dexamethasone- induced translocation of a serine phosphorylated species of ANXA1 from the cytoplasm to the outer cell surface. These results suggest that 1) the N-terminal domain plays a fundamental role in effecting the inhibitory actions of ANXA1 on pituitary peptide release; 2) PKC-dependent mechanisms are essential for both the cellular exportation and the biological activity of ANXA1; and 3) ANXA1 exported from the cells is serine phosphorylated.

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