The calcium-sensing receptor and its interacting proteins

Abstract

Seven membrane-spanning, or G protein-coupled receptors were originally thought to act through het-erotrimeric G proteins that in turn activate intracellular enzymes or ion channels, creating relatively simple, linear signalling pathways. Although this basic model remains true in that this family does act via a relatively small number of G proteins, these signalling systems are considerably more complex because the receptors interact with or are located near additional proteins that are often unique to a receptor or subset of receptors. These additional proteins give receptors their unique signalling personalities. The extracellular Ca-sensing receptor (CaR) signals via Galpha(i), Galpha(q) and Galpha(12/13), but its effects in vivo demonstrate that the signalling pathways controlled by these subunits are not sufficient to explain all its biologic effects. Additional structural or signalling proteins that interact with the CaR may explain its behaviour more fully. Although the CaR is less well studied in this respect than other receptors, several CaR-interacting proteins such as filamin, a potential scaffolding protein, receptor activity modifying proteins (RAMPs) and potassium channels may contribute to the unique characteristics of the CaR. The CaR also appears to interact with additional proteins common to other G protein-coupled receptors such as arrestins, G protein receptor kinases, protein kinase C, caveolin and proteins in the ubiquitination pathway. These proteins probably represent a few initial members of CaR-based signalling complex. These and other proteins may not all be associated with the CaR in all tissues, but they form the basis for understanding the complete nature of CaR signalling.

1

Four scenarios in which all G protein-coupled receptors interact with Gαβγ subunits that regulate standard second messenger generation and other common proteins (grey triangle, e.g. arrestin). They also interact with additional different proteins that give them unique signalling personalities. In A, the receptor interacts with filamin that itself binds additional proteins. The receptor shown in B interacts with an accessory protein (e.g. a RAMP) as well as another unique protein. The receptor shown in C has a long third intracellular loop that interacts with a unique protein (octagon), and a long C-terminus with a PDZ domain that binds a PDZ protein that itself brings additional proteins into the complex. In the scenario shown in D, the C-terminus of another membrane protein (e.g. a channel) interacts with the C-terminus of the receptor, and the receptor binds an additional protein.

2

A schematic diagram of the principal second messenger signalling pathways that have been described for the CaR. Most of these studies pathways were identified in heterologous expression systems, and may not all exist in all cells where the CaR is expressed at all times.