Weis Center for Research, Geisinger Clinic, 100 N. Academy Avenue, Danville, PA 17822-2604, USA.
Best Pract Res Clin Endocrinol Metab. 2013 Jun;27(3):303-13. doi: 10.1016/j.beem.2013.03.003. Epub 2013 Apr 19.
The calcium-sensing receptor (CaSR) must function in the chronic presence of agonist, and recent studies suggest that its ability to signal under such conditions depends upon the unique mechanism(s) regulating its cellular trafficking. This chapter will highlight the evidence supporting an intracellular endoplasmic reticulum-localized pool of CaSR that can be mobilized to the plasma membrane by CaSR signaling, leading to agonist-driven insertional signaling (ADIS). I summarize evidence for the role of small GTP binding proteins (Rabs, Sar1 and ARFs), cargo receptors or chaperones (p24A, RAMPs) and interacting proteins (14-3-3 proteins, calmodulin) in anterograde trafficking of CaSR, and discuss the potential signaling specializations arising from CaSR interactions with caveolins or Filamin A/Rho. Finally, I summarize current knowledge about CaSR endocytosis and degradation by both the proteasome and lysosome, and highlight recent studies indicating that defective trafficking of CaSR or interacting protein mutants contributes to pathology in disorders of calcium homeostasis.
钙敏感受体 (CaSR) 必须在激动剂的慢性存在下发挥作用，最近的研究表明，其在这种情况下进行信号传递的能力取决于调节其细胞内运输的独特机制。本章将重点介绍支持 CaSR 存在于细胞内内质网局部池的证据，该池可通过 CaSR 信号转导被动员到质膜，从而导致激动剂驱动的插入信号转导 (ADIS)。我总结了小 GTP 结合蛋白 (Rabs、Sar1 和 ARFs)、货物受体或伴侣蛋白 (p24A、RAMPs) 和相互作用蛋白 (14-3-3 蛋白、钙调蛋白) 在 CaSR 顺行运输中的作用的证据，并讨论了 CaSR 与 caveolins 或 Filamin A/Rho 相互作用产生的潜在信号专门化。最后，我总结了目前关于 CaSR 通过蛋白酶体和溶酶体进行内吞作用和降解的知识，并强调了最近的研究表明，CaSR 或相互作用蛋白突变体的运输缺陷导致钙稳态紊乱疾病的病理。
