TY - JOUR
T1 - Antagonism of Ca
2+
-sensing receptors by NPS 2143 is transiently masked by p38 activation in mouse brain bEND.3 endothelial cells
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
N1 - Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2019/1/1
Y1 - 2019/1/1
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.
KW - Ca -sensing receptors
KW - Endothelial cells
KW - NPS2143
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U2 - 10.1007/s00210-019-01637-y
DO - 10.1007/s00210-019-01637-y
M3 - Article
AN - SCOPUS:85062646890
SN - 0028-1298
VL - 392
SP - 823
EP - 832
JO - Naunyn-Schmiedeberg's Archives of Pharmacology
JF - Naunyn-Schmiedeberg's Archives of Pharmacology
IS - 7
ER -