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Heterodimerization of the Calcium-sensing receptor with the GabaB receptors in the breast.

乳房中钙敏感受体与 GabaB 受体的异二聚化。

基本信息

批准号：
10457479
负责人：
John J Wysolmerski
金额：
$ 41.81万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10457479
关键词：
3-Dimensional Adenylate Cyclase Affect Biology Biosensor Bone Resorption Breast Breast Cancer Cell Breast Epithelial Cells Calcium Calcium-Sensing Receptors Cells Cessation of life Couples Coupling Cyclic AMP Data Event Feedback Fluorescence Resonance Energy Transfer Functional disorder G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GABBR2 gene GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Gases Heterodimerization In Vitro Ion Transport Lactation MCF10A cells Mediating Membrane Milk Mus Nervous system structure Neurotransmitters Organ Physiology Production Protein Secretion Receptor Signaling Regulation Signal Transduction Skeleton System Techniques Therapeutic Time bone metabolism calcium metabolism cancer cell cell type dimer extracellular gamma-Aminobutyric Acid in vivo malignant breast neoplasm mammary mammary epithelium member milk production novel parathyroid hormone-related protein protein function receptor receptor expression receptor function response three dimensional cell culture tumor growth virtual

项目摘要

PROJECT SUMMARY/ABSTRACT The calcium-sensing receptor (CaSR) is a G protein-coupled receptor (GPCR) that signals in response to changes in extracellular calcium. It functions as an obligate dimer and couples to different G-proteins, including Gai or Gas, in a context- or cell type-specific manner. The CaSR is widely expressed and alters proliferation, differentiation, death and ion transport in a variety of cell types, including mammary epithelial cells (MECs), where it regulates the production of parathyroid hormone-related protein (PTHrP) and milk calcium transport. During lactation, activation of the CaSR on MECs inhibits PTHrP secretion by stimulating Gai and reducing cAMP levels. However, in breast cancer cells, activation of the CaSR increases, rather than decreases, PTHrP secretion because, in these cells, the CaSR activates Gas and increases cAMP levels. The CaSR has important functions in both lactation physiology and breast cancer pathophysiology, so it is critical to better understand the regulation of its downstream signaling events in breast epithelial cells. Emerging data demonstrate that the CaSR can heterodimerize with the 2 metabotropic, GabaB receptors, GABBR1 and GABBR2 and the central premise of this application is that heterodimerization of the CaSR with GABBR1 and/or GABBR2 alters CaSR signaling, PTHrP production and transepithelial calcium transport by mammary epithelial cells. Specifically, we hypothesize that, during lactation, reductions in GABBR1 expression and increases in GABBR2 expression promote the formation of CaSR/GABBR2 heterodimers in MECs, which, in turn, increases membrane CaSR expression and reinforces coupling of the CaSR to Gai. In order to explore this hypothesis, we propose 3 Specific Aims. Aim 1 will examine how heterodimerization with GABBR1 or GABBR2 alters CaSR expression, signaling and PTHrP production in breast epithelial cells in vitro. Aim 2 will use genetically modified mice to examine whether heterodimerization with GABBR2 regulates CaSR expression and function in the lactating breast in vivo. Aim 3 will use genetically modified mice to examine whether heterodimerization with GABBR1 regulates CaSR expression and function in the lactating breast in vivo. The studies outlined in this proposal will explore novel biology of great importance for lactation physiology that also has implications for breast cancer pathophysiology. These studies have the potential to discover novel ways to target the CaSR therapeutically.

项目总结/文摘