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Published on: May 19, 2017
Calcium-sensing receptor (CaSR): pharmacological properties and signaling pathways
Arthur D Conigrave1, Donald T Ward
1School of Molecular Bioscience, University of Sydney, NSW 2006, Australia. arthur.conigrave@sydney.edu.au
Abstract:
In this article we consider the mechanisms by which the calcium-sensing receptor (CaSR) induces its cellular responses via the control (activation or inhibition) of signaling pathways. We consider key features of CaSR-mediated signaling including its control of the heterotrimeric G-proteins Gq/11, Gi/o and G12/13 and the downstream consequences recognizing that very few CaSR-mediated cell phenomena have been fully described. We also consider the manner in which the CaSR contributes to the formation of specific signaling scaffolds via peptide recognition sequences in its intracellular C-terminal along with the origins of its high level of cooperativity, particularly for Ca(2+)o, and its remarkable resistance to desensitization. We also consider the nature of the mechanisms by which the CaSR controls oscillatory and sustained Ca(2+)i mobilizing responses and inhibits or elevates cyclic adenosine monophosphate (cAMP) levels dependent on the cellular and signaling context. Finally, we consider the diversity of the receptor's ligands, ligand binding sites and broader compartment-dependent physiological roles leading to the identification of pronounced ligand-biased signaling for agonists including Sr(2+) and modulators including l-amino acids and the clinically effective calcimimetic cinacalcet. We note the implications of these findings for the development of new designer drugs that might target the CaSR in pathophysiological contexts beyond those established for the treatment of disorders of calcium metabolism.
Insights
The calcium-sensing receptor (CaSR) controls cellular responses by modulating signaling pathways, including G-protein activation and cyclic adenosine monophosphate (cAMP) levels. Understanding CaSR mechanisms offers potential for new drug development beyond calcium metabolism disorders.
Area of Science:
- Cellular signaling
- Molecular biology
- Pharmacology
Background:
- The calcium-sensing receptor (CaSR) is a key regulator of cellular responses.
- CaSR signaling involves complex interactions with G-proteins and downstream pathways.
- Limited understanding exists for many CaSR-mediated cellular phenomena.
Purpose of the Study:
- To elucidate the mechanisms of CaSR-induced cellular responses.
- To explore CaSR's control over various signaling pathways and G-proteins (Gq/11, Gi/o, G12/13).
- To investigate CaSR's role in signaling scaffold formation, cooperativity, and desensitization resistance.
Main Methods:
- Analysis of CaSR's interaction with heterotrimeric G-proteins.
- Investigation of CaSR's C-terminal signaling scaffold formation.
- Examination of CaSR's control over intracellular calcium (Ca(2+)i) and cyclic adenosine monophosphate (cAMP) levels.
- Study of diverse CaSR ligands, binding sites, and biased signaling.
Main Results:
- CaSR modulates Gq/11, Gi/o, and G12/13 signaling pathways with varied downstream effects.
- CaSR forms signaling scaffolds via its C-terminal peptide recognition sequences.
- CaSR exhibits high cooperativity for extracellular calcium (Ca(2+)o) and resistance to desensitization.
- CaSR controls oscillatory and sustained intracellular calcium mobilization and cAMP levels.
- Ligand-biased signaling is observed for CaSR agonists (e.g., Sr(2+)) and modulators (e.g., cinacalcet).
Conclusions:
- CaSR signaling is complex, involving diverse G-proteins and context-dependent modulation of cAMP.
- CaSR's structural features contribute to its high cooperativity and desensitization resistance.
- Understanding CaSR ligand interactions and biased signaling opens avenues for novel therapeutic strategies.
- Findings have implications for developing CaSR-targeting drugs for conditions beyond calcium metabolism disorders.
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