Synaptotagmin isoforms regulate hormone secretion in the anterior pituitary.

摘要

The ability of cells to regulate the differential release of multiple signaling molecules is of significant interest and the theory that different isoforms of synaptotagmin (syt) could be the mechanism for these distinct profiles of release is a relatively new idea. The syts are a family of evolutionarily conserved Ca2+-sensing proteins and the founding family member, syt-1, is localized to synaptic vesicle (SV) membranes and is essential for the fast component of exocytosis in neurons. However, there are 16 additional family members some of which are Ca2+-activated isoforms with specific Ca2+, lipid binding, and kinetic properties where as other isoforms of syt are capable of inhibiting fusion. Current data also suggests that most isoforms are associated with the exocytosis of secretory organelles other than SVs; including hormone containing large dense core vesicles (LDCV)s. Therefore, we investigated the role of syts in the richest hormone releasing tissue, the pituitary gland, which controls numerous essential functions in physiology. We revealed that multiple syt isoforms are present and highly expressed in the pituitary gland, with some isoforms exhibiting lobe specific expression patterns within the pituitary. More specifically, we revealed that syt-9 is highly co-localized with follicle stimulating hormone (FSH) containing granules in gonadotropic cells and acts as a Ca2+ sensor for release in female, but not male, mice; the loss of which leads to an altered estrous cycle. In thyroid stimulating hormone (TSH) releasing cells, we demonstrate that syt-9 once again serves as a Ca2+ sensor for hormone release in females and that syt-11, an inhibitory isoform of syt, negatively regulates the release of TSH in males. The loss of syt-9 and syt-11 led to hypo and hypersecretion phenotypes in female and male mice, respectively, which was accompanied by appropriate changes in body weight. As a whole, this thesis defines a functional role for syts in pituitary hormone secretion, reveals novel molecular mechanisms controlling FSH and TSH exocytosis, and uncovers novel sex-specific difference in hormone release.