当前位置： SCI文献检索 > JOURNAL OF PHARMACOLOGICAL SCIENCES期刊下所有文献 > Differential coupling of human endothelin type A receptor to G(q/11) and G(12) proteins: the functional significance of receptor expression level in generating multiple receptor signaling.

Differential coupling of human endothelin type A receptor to G(q/11) and G(12) proteins: the functional significance of receptor expression level in generating multiple receptor signaling.

Abstract：

:This study examines the influence of receptor expression level on signaling pathways activated via endothelin type A receptor (ET(A)R) expressed in Chinese hamster ovary cells at 32,100 (ET(A)R-high-CHO) and 893 (ET(A)R-low-CHO) fmolmg protein(-1). Endothelin-1 (ET-1) elicited a sustained increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), which was dependent on G(q/11) protein, phospholipase C (PLC), Na(+)/H(+) exchanger (NHE), and p38 mitogen-activated protein kinase (p38MAPK) in ET(A)R-high-CHO, whereas the sustained [Ca(2+)](i) increase was negligible in ET(A)R-low-CHO. Functional study with Cytosensor(TM) microphysiometer showed that ET-1 evoked an NHE1-mediated increase in extracellular acidification rate (ECAR) in ET(A)R-high-CHO and ET(A)R-low-CHO. In ET(A)R-high-CHO, the ECAR response at 30 min after ET-1 stimulation was insensitive to G(q/11) and PLC inhibitors, but sensitive to the p38MAPK inhibitor. In ET(A)R-low-CHO, the ECAR response at 30 min was sensitive to these inhibitors. Western blot analysis demonstrated that ET-1-induced p38MAPK phosphorylation in ET(A)R-low-CHO but not in ET(A)R-high-CHO was mediated via G(q/11) and PLC. The G(q/11)/PLC-independent p38MAPK phosphorylation in ET(A)R-high-CHO was suppressed by expression of the C terminus of G(alpha12) protein to disrupt receptor-G(12) protein coupling. These results provide evidence for multiple signaling pathways of ET(A)R that were activated via at least the G(q/11)/PLC/NHE, G(12)/p38MAPK/NHE, and G(q/11)/PLC/p38MAPK/NHE cascades in an expression level-dependent manner.

journal_name

J Pharmacol Sci

journal_title

Journal of pharmacological sciences

authors

Horinouchi T,Asano H,Higa T,Nishimoto A,Nishiya T,Muramatsu I,Miwa S

doi

10.1254/jphs.09233fp

subject

Has Abstract

pub_date

2009-12-01 00:00:00

pages

338-51

issue

4

eissn

1347-8613

issn

1347-8648

pii

JST.JSTAGE/jphs/09233FP

journal_volume

111

pub_type

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