scholarly journals Direct Determination of Multiple Ligand Interactions with the Extracellular Domain of the Calcium-sensing Receptor

2014 ◽  
Vol 289 (48) ◽  
pp. 33529-33542 ◽  
Author(s):  
Chen Zhang ◽  
You Zhuo ◽  
Heather A. Moniz ◽  
Shuo Wang ◽  
Kelley W. Moremen ◽  
...  
Keyword(s):  
Direct Determination ◽  
Extracellular Domain ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing ◽  
Ligand Interactions ◽  
Multiple Ligand

Peptide Blocking Self-Polymerization of Extracellular Calcium-Sensing Receptor Attenuates Hypoxia-Induced Pulmonary Hypertension

Hypertension ◽  
2021 ◽  
Author(s):  
Rui Xiao ◽  
Shengquan Luo ◽  
Ting Zhang ◽  
Yankai Lv ◽  
Tao Wang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Disulfide Bonds ◽  
Acute Hypoxia ◽  
Extracellular Domain ◽  
Left Ventricular ◽  
Extracellular Calcium ◽  
Calcium Sensing Receptor ◽  
Calcium Sensing

Activation of the CaSR (extracellular calcium-sensing receptor) has been recognized as a critical mediator of hypoxia-induced pulmonary hypertension. Preventive targeting of the early initiating phase as well as downstream events after CaSR activation remains unexplored. As a representative of the G protein-coupled receptor family, CaSR polymerizes on cell surface upon stimulation. Immunoblotting together with MAL-PEG technique identified a reactive oxygen species-sensitive CaSR polymerization through its extracellular domain in pulmonary artery smooth muscle cells upon exposure to acute hypoxia. Fluorescence resonance energy transfer screening employing blocking peptides determined that cycteine129/131 residues in the extracellular domain of CaSR formed intermolecular disulfide bonds to promote CaSR polymerization. The monitoring of intracellular Ca 2+ signal highlighted the pivotal role of CaSR polymerization in its activation. In contrast, the blockade of disulfide bonds formation using a peptide decreased both CaSR and hypoxia-induced mitogenic factor expression as well as other hypoxic-related genes in vitro and in vivo and attenuated pulmonary hypertension development in rats. The blocking peptide did not affect systemic arterial oxygenation in vivo but inhibited acute hypoxia-induced pulmonary vasoconstriction. Pharmacokinetic analyses revealed a more efficient lung delivery of peptide by inhaled nebulizer compared to intravenous injection. In addition, the blocking peptide did not affect systemic arterial pressure, body weight, left ventricular function, liver, or kidney function or plasma Ca 2+ level. In conclusion, a peptide blocking CaSR polymerization reduces its hypoxia-induced activation and downstream events leading to pulmonary hypertension and represents an attractive inhaled preventive alternative worthy of further development.

Hypercalcaemia

2011 ◽  
pp. 642-652
Author(s):  
Ronen Levi ◽  
Justin Silver
Keyword(s):  
Extracellular Fluid ◽  
Immune Functions ◽  
Calcium Sensing Receptor ◽  
Neuromuscular Activation ◽  
Plasma Coagulation ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Calcium Sensing ◽  
Life Threatening

Ionized calcium is essential for several physiological functions, including neuromuscular activation, endocrine and exocrine secretions, integrity of cellular bilayers, plasma coagulation, immune functions and bone metabolism. Extracellular fluid (ECF) calcium is uniquely controlled by its own calcium-sensing receptor, regulating the secretion of parathyroid hormone (PTH), synthesis of 1,25-dihydroxyvitamin D, and the renal reabsorption of filtered calcium (see Chapter 4.1). With the advent of the autoanalyser and routine determination of serum calcium levels, recognition of hypercalcaemia has become common. However, the clinical spectrum of hypercalcaemia varies from a laboratory-detected, asymptomatic mineral disorder to a life-threatening state.

scholarly journals Structural mechanism of ligand activation in human calcium-sensing receptor

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Yong Geng ◽  
Lidia Mosyak ◽  
Igor Kurinov ◽  
Hao Zuo ◽  
Emmanuel Sturchler ◽  
...  
Keyword(s):  
Structural Integrity ◽  
Hormone Secretion ◽  
Extracellular Domain ◽  
Receptor Activation ◽  
Activation Mechanism ◽  
Calcium Sensing Receptor ◽  
Structural Mechanism ◽  
Active Structure ◽  
Rich Domain ◽  
Calcium Sensing

Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that maintains extracellular Ca2+ homeostasis through the regulation of parathyroid hormone secretion. It functions as a disulfide-tethered homodimer composed of three main domains, the Venus Flytrap module, cysteine-rich domain, and seven-helix transmembrane region. Here, we present the crystal structures of the entire extracellular domain of CaSR in the resting and active conformations. We provide direct evidence that L-amino acids are agonists of the receptor. In the active structure, L-Trp occupies the orthosteric agonist-binding site at the interdomain cleft and is primarily responsible for inducing extracellular domain closure to initiate receptor activation. Our structures reveal multiple binding sites for Ca2+ and PO43- ions. Both ions are crucial for structural integrity of the receptor. While Ca2+ ions stabilize the active state, PO43- ions reinforce the inactive conformation. The activation mechanism of CaSR involves the formation of a novel dimer interface between subunits.

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