Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 8, Pages 5296-5309Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.537357
Keywords
Amino Acid; Calcium Imaging; Calcium Signaling; Cooperativity; G Protein-coupled Receptors (GPCR); Calcium-sensing Receptor; Calcium Oscillation
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Funding
- National Institutes of Health [GM081749, EB007268]
- National Science Foundation [MCB-0953061]
- Center for Diagnostics and Therapeutics (CDT) fellowship
- Georgia Research Alliance
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [0953061] Funding Source: National Science Foundation
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Background: The calcium-sensing receptor (CaSR) is a key mediator of Ca2+ homeostasis in vivo. Results: An l-Phe binding site at the CaSR hinge region globally enhances its cooperative activation by Ca2+. Conclusion: Communication between the binding sites for Ca2+ and l-Phe is crucial for functional cooperativity of CaSR-mediated signaling. Significance: The results provide important insights into the molecular basis of Ca2+ sensing by the CaSR. Functional positive cooperative activation of the extracellular calcium ([Ca2+](o))-sensing receptor (CaSR), a member of the family C G protein-coupled receptors, by [Ca2+](o) or amino acids elicits intracellular Ca2+ ([Ca2+](i)) oscillations. Here, we report the central role of predicted Ca2+-binding site 1 within the hinge region of the extracellular domain (ECD) of CaSR and its interaction with other Ca2+-binding sites within the ECD in tuning functional positive homotropic cooperativity caused by changes in [Ca2+](o). Next, we identify an adjacent l-Phe-binding pocket that is responsible for positive heterotropic cooperativity between [Ca2+](o) and l-Phe in eliciting CaSR-mediated [Ca2+](i) oscillations. The heterocommunication between Ca2+ and an amino acid globally enhances functional positive homotropic cooperative activation of CaSR in response to [Ca2+](o) signaling by positively impacting multiple [Ca2+](o)-binding sites within the ECD. Elucidation of the underlying mechanism provides important insights into the longstanding question of how the receptor transduces signals initiated by [Ca2+](o) and amino acids into intracellular signaling events.
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