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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

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.
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fig02: 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.

Mentions: Most work on the signalling pathways controlled by the CaR has focused on traditional G protein-coupled pathways, Gαi, Gαq, and in some cases Gα12 or Gα13[1, 12–16] (Fig. 2). Through Gαi, the CaR inhibits adenylyl cyclase and activates extracellular signal-regulated kinase (ERK), through Gαq it activates phos-pholipase C, increases Cai and DAG (diacyl glycerol) levels, and activates phospholipase A2, and through Gα12/13, it activates Rho and phospholipase D [17]. Although the full physiologic significance is not understood, activation of the CaR initiates Ca oscillations via a Gαq-dependent mechanism that when prolonged or forming a plateau, inhibit adenylyl cyclase activity co-ordinately with Gαi activation [14]. This system serves as an active turn-off system for cAMP signals and depends on the forms of adenylyl cyclase expressed in different tissues. In the intestine, the CaR inhibits cholera toxin and E. coli heat stable enterotox-in-stimulated fluid secretion via activation of cyclic nucleotide phosphodiesterases and inhibition of NKCC1 (sodium, potassium, 2Cl transporter-1) activity [18]. In keeping with studies of other G protein-coupled receptors, the CaR transactivates, the epidermal growth factor receptor presumably via a matrix metal-loproteinase [19, 20]. In different regions of the nephron and gastro-intestinal tract, the CaR is expressed on apical or basolateral membranes of epithelial cells where it is likely to come into contact with distinct sets of proteins that should give the CaR different signalling characteristics and biologic effects. Similarly, the CaR is expressed in many different cell types with different functions, so its signalling and biologic functions could vary from cell type to cell type.


The calcium-sensing receptor and its interacting proteins.

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

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.
© Copyright Policy
Related In: Results  -  Collection

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

fig02: 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.
Mentions: Most work on the signalling pathways controlled by the CaR has focused on traditional G protein-coupled pathways, Gαi, Gαq, and in some cases Gα12 or Gα13[1, 12–16] (Fig. 2). Through Gαi, the CaR inhibits adenylyl cyclase and activates extracellular signal-regulated kinase (ERK), through Gαq it activates phos-pholipase C, increases Cai and DAG (diacyl glycerol) levels, and activates phospholipase A2, and through Gα12/13, it activates Rho and phospholipase D [17]. Although the full physiologic significance is not understood, activation of the CaR initiates Ca oscillations via a Gαq-dependent mechanism that when prolonged or forming a plateau, inhibit adenylyl cyclase activity co-ordinately with Gαi activation [14]. This system serves as an active turn-off system for cAMP signals and depends on the forms of adenylyl cyclase expressed in different tissues. In the intestine, the CaR inhibits cholera toxin and E. coli heat stable enterotox-in-stimulated fluid secretion via activation of cyclic nucleotide phosphodiesterases and inhibition of NKCC1 (sodium, potassium, 2Cl transporter-1) activity [18]. In keeping with studies of other G protein-coupled receptors, the CaR transactivates, the epidermal growth factor receptor presumably via a matrix metal-loproteinase [19, 20]. In different regions of the nephron and gastro-intestinal tract, the CaR is expressed on apical or basolateral membranes of epithelial cells where it is likely to come into contact with distinct sets of proteins that should give the CaR different signalling characteristics and biologic effects. Similarly, the CaR is expressed in many different cell types with different functions, so its signalling and biologic functions could vary from cell type to cell type.

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