Anterior pituitary (AP) cells are excitable cells; displaying cell-type specific spontaneous and stimulated rhythmic electrical activity. This electrical activity is generated by a repertoire of voltage-gated channels that are differently expressed in different pituitary cell-types. The voltage-gated Ca2+ influx (VGCI), which is coupled to this rhythmic electrical activity, plays a pivotal role in the secretion of AP hormones. This electrical activity and VGCI in AP cells is constantly regulated by complex arrays of hypothalamic releasing-hormones (RHs) and peripheral hormones. We are studying biophysical, pharmacological and functional properties of this VGCI in rat AP cells; in growth-hormone secreting cells (somatotrophs) and in prolactin secreting cells (lactotrophs).
We recently revealed that this VGCI in somatotrophs and lactotrophs is carried through at least 5 Ca2+channel pathways (Cav1.2, Cav1.3, Cav2.1, Cav2.2 and Cav2.3), and that these 5 pathways are segregated among raft and nonraft membrane lipid microdomains; Cav1.2, and Cav2.1 in raft domains, Cav2.2 and Cav2.3 in nonraft domains and Cav1.3 among raft and nonraft domains. Additionally, we revealed that the functional properties of Ca2+ channels in somatotrophs and lactotrophs are significantly altered by perturbation in their lipid microenvironment. This compartmentalization of Ca2+ channels among raft and nonraft lipid domains is expected to provide a subcellular mechanism for differential regulation of VGCI (by RHs), and therefore of hormone-secretion, under different physiological, hormonal, or pathological conditions.
We plan to investigate the importance of lipid rafts and caveolae in the secretion of pituitary hormones, hypothesizing that these lipid microdomains serve as subcellular platforms for differential regulation of AP hormone secretion (by RHs). We are currently investigating the lateral segregation of Ca2+ channels among caveolar and non-caveolar raft domains and the functional implication of this segregation to the secretion of GH and Prolactin. We will next examine whether GPCRs (RHs which regulate GH and Prolactin secretion) and their cognate signaling pathways co-localize with Ca2+ channels in lipid raft domains. At a longer run, we plan to investigate whether lipid microdomains determine the spatial organization of hormone release sites, being membrane anchors for co-localization of Ca2+ channels and the exocytotic machinery (SNAREs).
· Co-localization of Ca2+ channels, Caveolins and SNARE proteins in lipid microdomains.
· The role of caveolin-1 in regulating Ca2+ channel function and pituitary hormone release.
· Localization of GHRH receptors, Somatostatin receptors and Dopamine receptors in lipid rafts.
· The role of membrane lipids (cholesterol, sphingolipids) in regulating Ca2+ channel function.
Elad Sosial-MSc student.
Tzour A, Sosial E, Meir T, Canello T, Naveh-Many T, Gabizon R and Nussinovitch I (2013). Multiple pathways for high voltage-activated Ca2+ influx in anterior pituitary lactotrophs and somatotrophs. J Neuroendocrinology 25, 76-86
Ben-Zeev G, Telias M and Nussinovitch I (2010). Lysophospholipids modulate voltage-gated Ca2+ channel currents in pituitary cells; effects of lipid stress. Cell Calcium 47: 514-524,
Ben-Tabou De-Leon S, Ben-Zeev G and Nussinovitch I (2006). Effects of osmotic shrinkage on voltage-gated Ca2+ channel currents in rat anterior pituitary cells. Am J Physiol Cell Physiol 290: C222-C232.
Ben-Tabou De-Leon S, Blotnick E and Nussinovitch I (2003). Effects of osmotic swelling on voltage-gated Ca2+ channel currents in rat anterior pituitary cells. Am J Physiol Cell Physiol 285: C840-C852.