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Comparison of MEK/ERK pathway inhibitors on the upregulation of vascular G-protein coupled receptors in rat cerebral arteries.

Abstract：

:Organ culture is an in vitro method for investigating cellular mechanisms involved in upregulation of vasocontractile G-protein coupled receptors. We hypothesize that mitogen-activated-protein kinase (MEK) and/or extracellular-signal-regulated kinase (ERK) specific inhibitors will attenuate the G-protein coupled receptor expression following organ culture. Rat cerebral arteries were incubated 48h in the presence of MEK/ERK specific inhibitors U0126, PD98059, SL327, or AG126 for different time periods. Contractile responses by activation of endothelin receptor type A and type B, serotonin receptor 5-HT(1B), prostanoid TP receptor, and angiotensin II receptor type 1 and type 2 were investigated. Results were verified by measurement of mRNA with real time PCR and by protein immunohistochemistry. Organ culture induced transcriptional upregulation of endothelin ET(B) receptor and of serotonin 5-HT(1B) receptor on translational level and increased respective contractions. The prostanoid TP receptor mediated contraction curve was left-wards shifted by organ culture. Organ culture was associated with elevated pERK1/2 in the vascular smooth muscle cells: the MEK1/2 inhibitor U0126 attenuated the endothelin ET(B) receptor mediated contraction at post-translational level or by changing the receptor affinities. The serotonin 5-HT(1B) receptor and prostanoid TP receptor mediated contractions were abolished by U0126. Administration of U0126 6h after start of incubation blocked the receptor upregulation. In conclusion, MEK specific inhibitor U0126 is a potent inhibitor of G-protein coupled receptor alteration seen during organ culture. Given the ability to inhibit G-protein coupled receptor alteration at the clinically relevant time-point 6h post incubation makes it an attractive therapeutic agent for in vivo studies.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Sandhu H,Ansar S,Edvinsson L

doi

10.1016/j.ejphar.2010.06.053

subject

Has Abstract

pub_date

2010-10-10 00:00:00

pages

128-37

issue

1-3

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(10)00661-8

journal_volume

644

pub_type

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Comparison of MEK/ERK pathway inhibitors on the upregulation of vascular G-protein coupled receptors in rat cerebral arteries.