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The calcium-sensing receptor and its interacting proteins.

Huang C, Miller RT - J. Cell. Mol. Med. (2007 Sep-Oct)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Physiology, Case-Western Reserve University, Louis Stokes VAMC Rammelkamp Center for Research, Metro Health Medical Center, Cleveland, Ohio, USA.

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.

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Related in: MedlinePlus

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.
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fig01: 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.

Mentions: The original model of signalling by G protein-dependent receptors was relatively simple. The receptors and G proteins through which the intracellular second messenger systems are activated are attached to the plasma membrane of the cell. These proteins could be relatively free in the membrane or loosely associated with each other. Upon activation of a receptor, the protein interactions change, G proteins are activated, which in turn activate effector molecules such as enzymes or ion channels, to generate intracellular signals (Fig. 1). As techniques to identify protein–protein interactions have been developed and as more precise analysis of cell signalling has become possible, the inadequacy of the original model has become clear through demonstration that G protein-coupled receptors interact with many intracellular proteins in addition to G proteins. These interacting proteins include RGS proteins (Regulator of G protein Signalling), scaffolding and structural proteins, ion channels, additional signalling proteins, chaperone and trafficking proteins and others that may not have defined functions yet [8–11]. Receptors that act through similar sets of G proteins may have different signalling or biologic effects in different regions of a cell and in different cells. This finding suggests that they may have common activities based on the G proteins with which they interact, but that they may also have distinct functions based on the unique sets of other proteins with which they interact as well as their unique locations within a cell. Although no one receptor in a native tissue has been characterized completely, enough work has been done with different receptors including the 2-, -adrenergic and metabotropic glutamate receptors in various experimental systems to indicate that such a scenario is not only plausible, but likely (Fig. 1) [9–11].


The calcium-sensing receptor and its interacting proteins.

Huang C, Miller RT - J. Cell. Mol. Med. (2007 Sep-Oct)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401264&req=5

fig01: 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.
Mentions: The original model of signalling by G protein-dependent receptors was relatively simple. The receptors and G proteins through which the intracellular second messenger systems are activated are attached to the plasma membrane of the cell. These proteins could be relatively free in the membrane or loosely associated with each other. Upon activation of a receptor, the protein interactions change, G proteins are activated, which in turn activate effector molecules such as enzymes or ion channels, to generate intracellular signals (Fig. 1). As techniques to identify protein–protein interactions have been developed and as more precise analysis of cell signalling has become possible, the inadequacy of the original model has become clear through demonstration that G protein-coupled receptors interact with many intracellular proteins in addition to G proteins. These interacting proteins include RGS proteins (Regulator of G protein Signalling), scaffolding and structural proteins, ion channels, additional signalling proteins, chaperone and trafficking proteins and others that may not have defined functions yet [8–11]. Receptors that act through similar sets of G proteins may have different signalling or biologic effects in different regions of a cell and in different cells. This finding suggests that they may have common activities based on the G proteins with which they interact, but that they may also have distinct functions based on the unique sets of other proteins with which they interact as well as their unique locations within a cell. Although no one receptor in a native tissue has been characterized completely, enough work has been done with different receptors including the 2-, -adrenergic and metabotropic glutamate receptors in various experimental systems to indicate that such a scenario is not only plausible, but likely (Fig. 1) [9–11].

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Physiology, Case-Western Reserve University, Louis Stokes VAMC Rammelkamp Center for Research, Metro Health Medical Center, Cleveland, Ohio, USA.

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.

Show MeSH
Related in: MedlinePlus