Antagonism of Ca 2+ -sensing receptors by NPS 2143 is transiently masked by p38 activation in mouse brain bEND.3 endothelial cells

Cing Yu Chen, Mann Jen Hour, Wen Chuan Lin, Kar Lok Wong, Lian Ru Shiao, Ka Shun Cheng, Paul Chan, Yuk Man Leung

Research output: Contribution to journalArticle

Abstract

Ca 2+ -sensing receptors (CaSR) are G protein-coupled receptors which are activated by a rise in extracellular Ca 2+ . CaSR activation has been known to inhibit parathyroid hormone release and stimulate calcitonin release from parathyroid glands and thyroid parafollicular C cells, respectively. The roles of CaSR in other cell types including endothelial cells (EC) are much less understood. In this work, we demonstrated protein and functional expression of CaSR in mouse cerebral EC (bEND.3). Unexpectedly, CaSR response (high Ca 2+ -elicited cytosolic [Ca 2+ ] elevation) was unaffected by edelfosine or U73122 but strongly suppressed by SK&F 96365, ruthenium red, and 2-aminoethoxydiphenyl borate (2-APB), suggesting involvement of TRPV and TRPC channels but not Gq-phospholipase C. Acute application of NPS2143, a negative allosteric modulator of CaSR, suppressed CaSR response. However, a 40-min NPS2143 pre-treatment surprisingly enhanced CaSR response. After 4–24 h of application, this enhancement faded away and suppression of CaSR response was observed again. Similar results were obtained when La 3+ and Sr 2+ were used as CaSR agonists. The transient NPS 2143 enhancement effect was abolished by SB203580, a p38 inhibitor. Consistently, NPS 2143 triggered a transient p38 activation. Taken together, results suggest that in bEND.3 cells, NPS 2143 caused acute suppression of CaSR response, but then elicited a transient enhancement of CaSR response in a p38-dependent manner. NPS 2143 effects on CaSR in bEND.3 cells therefore depended on drug exposure time. These findings warrant cautious use of this agent as a CaSR modulator and potential cardiovascular drug.

Original languageEnglish
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
DOIs
Publication statusPublished - Jan 1 2019

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Calcium-Sensing Receptors
Endothelial Cells
Brain
N-(2-hydroxy-3-(2-cyano-3-chlorophenoxy)propyl)-1,1-dimethyl-2-(2-nephthyl)ethylamine
Cardiovascular Agents
Ruthenium Red
Parathyroid Glands
Calcitonin
Type C Phospholipases
G-Protein-Coupled Receptors
Parathyroid Hormone

Keywords

  • Ca -sensing receptors
  • Endothelial cells
  • NPS2143

ASJC Scopus subject areas

  • Pharmacology

Cite this

Antagonism of Ca 2+ -sensing receptors by NPS 2143 is transiently masked by p38 activation in mouse brain bEND.3 endothelial cells. / Chen, Cing Yu; Hour, Mann Jen; Lin, Wen Chuan; Wong, Kar Lok; Shiao, Lian Ru; Cheng, Ka Shun; Chan, Paul; Leung, Yuk Man.

In: Naunyn-Schmiedeberg's Archives of Pharmacology, 01.01.2019.

Research output: Contribution to journalArticle

Chen, Cing Yu ; Hour, Mann Jen ; Lin, Wen Chuan ; Wong, Kar Lok ; Shiao, Lian Ru ; Cheng, Ka Shun ; Chan, Paul ; Leung, Yuk Man. / Antagonism of Ca 2+ -sensing receptors by NPS 2143 is transiently masked by p38 activation in mouse brain bEND.3 endothelial cells. In: Naunyn-Schmiedeberg's Archives of Pharmacology. 2019.
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abstract = "Ca 2+ -sensing receptors (CaSR) are G protein-coupled receptors which are activated by a rise in extracellular Ca 2+ . CaSR activation has been known to inhibit parathyroid hormone release and stimulate calcitonin release from parathyroid glands and thyroid parafollicular C cells, respectively. The roles of CaSR in other cell types including endothelial cells (EC) are much less understood. In this work, we demonstrated protein and functional expression of CaSR in mouse cerebral EC (bEND.3). Unexpectedly, CaSR response (high Ca 2+ -elicited cytosolic [Ca 2+ ] elevation) was unaffected by edelfosine or U73122 but strongly suppressed by SK&F 96365, ruthenium red, and 2-aminoethoxydiphenyl borate (2-APB), suggesting involvement of TRPV and TRPC channels but not Gq-phospholipase C. Acute application of NPS2143, a negative allosteric modulator of CaSR, suppressed CaSR response. However, a 40-min NPS2143 pre-treatment surprisingly enhanced CaSR response. After 4–24 h of application, this enhancement faded away and suppression of CaSR response was observed again. Similar results were obtained when La 3+ and Sr 2+ were used as CaSR agonists. The transient NPS 2143 enhancement effect was abolished by SB203580, a p38 inhibitor. Consistently, NPS 2143 triggered a transient p38 activation. Taken together, results suggest that in bEND.3 cells, NPS 2143 caused acute suppression of CaSR response, but then elicited a transient enhancement of CaSR response in a p38-dependent manner. NPS 2143 effects on CaSR in bEND.3 cells therefore depended on drug exposure time. These findings warrant cautious use of this agent as a CaSR modulator and potential cardiovascular drug.",
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AU - Chen, Cing Yu

AU - Hour, Mann Jen

AU - Lin, Wen Chuan

AU - Wong, Kar Lok

AU - Shiao, Lian Ru

AU - Cheng, Ka Shun

AU - Chan, Paul

AU - Leung, Yuk Man

PY - 2019/1/1

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N2 - Ca 2+ -sensing receptors (CaSR) are G protein-coupled receptors which are activated by a rise in extracellular Ca 2+ . CaSR activation has been known to inhibit parathyroid hormone release and stimulate calcitonin release from parathyroid glands and thyroid parafollicular C cells, respectively. The roles of CaSR in other cell types including endothelial cells (EC) are much less understood. In this work, we demonstrated protein and functional expression of CaSR in mouse cerebral EC (bEND.3). Unexpectedly, CaSR response (high Ca 2+ -elicited cytosolic [Ca 2+ ] elevation) was unaffected by edelfosine or U73122 but strongly suppressed by SK&F 96365, ruthenium red, and 2-aminoethoxydiphenyl borate (2-APB), suggesting involvement of TRPV and TRPC channels but not Gq-phospholipase C. Acute application of NPS2143, a negative allosteric modulator of CaSR, suppressed CaSR response. However, a 40-min NPS2143 pre-treatment surprisingly enhanced CaSR response. After 4–24 h of application, this enhancement faded away and suppression of CaSR response was observed again. Similar results were obtained when La 3+ and Sr 2+ were used as CaSR agonists. The transient NPS 2143 enhancement effect was abolished by SB203580, a p38 inhibitor. Consistently, NPS 2143 triggered a transient p38 activation. Taken together, results suggest that in bEND.3 cells, NPS 2143 caused acute suppression of CaSR response, but then elicited a transient enhancement of CaSR response in a p38-dependent manner. NPS 2143 effects on CaSR in bEND.3 cells therefore depended on drug exposure time. These findings warrant cautious use of this agent as a CaSR modulator and potential cardiovascular drug.

AB - Ca 2+ -sensing receptors (CaSR) are G protein-coupled receptors which are activated by a rise in extracellular Ca 2+ . CaSR activation has been known to inhibit parathyroid hormone release and stimulate calcitonin release from parathyroid glands and thyroid parafollicular C cells, respectively. The roles of CaSR in other cell types including endothelial cells (EC) are much less understood. In this work, we demonstrated protein and functional expression of CaSR in mouse cerebral EC (bEND.3). Unexpectedly, CaSR response (high Ca 2+ -elicited cytosolic [Ca 2+ ] elevation) was unaffected by edelfosine or U73122 but strongly suppressed by SK&F 96365, ruthenium red, and 2-aminoethoxydiphenyl borate (2-APB), suggesting involvement of TRPV and TRPC channels but not Gq-phospholipase C. Acute application of NPS2143, a negative allosteric modulator of CaSR, suppressed CaSR response. However, a 40-min NPS2143 pre-treatment surprisingly enhanced CaSR response. After 4–24 h of application, this enhancement faded away and suppression of CaSR response was observed again. Similar results were obtained when La 3+ and Sr 2+ were used as CaSR agonists. The transient NPS 2143 enhancement effect was abolished by SB203580, a p38 inhibitor. Consistently, NPS 2143 triggered a transient p38 activation. Taken together, results suggest that in bEND.3 cells, NPS 2143 caused acute suppression of CaSR response, but then elicited a transient enhancement of CaSR response in a p38-dependent manner. NPS 2143 effects on CaSR in bEND.3 cells therefore depended on drug exposure time. These findings warrant cautious use of this agent as a CaSR modulator and potential cardiovascular drug.

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