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Gαi and Gβγ subunits have opposing effects on dexmedetomidine-induced sedation.

Abstract：

:Dexmedetomidine (DMED) is a potent and highly selective α2-adrenergic receptor agonist and is widely used for short-term sedation. However, the mechanism of DMED-induced sedation has not been deciphered. In the present study, we investigated the mechanism of Gαi and Gβγ subunits on DMED-induced sedation. An ED50 of DMED-induced loss of righting reflex (200.0nmol/kg) was increased to 375.0 or 433.3nmol/kg after pre-treatment with cAMP analog dbcAMP (50nmol/5 μl/mouse, i.c.v.) or the phosphodiesterase 4 inhibitor rolipram (100nmol/5 μl/mouse, i.c.v.). Conversely, the ED50 of DMED-induced LORR decreased to 113.6 or 136.5 nmol/kg after pre-treated with Gβγ subunit inhibitor M119 (100 mg/kg, i.p.) or gallein (100 mg/kg, i.p.) respectively. Administration of dbcAMP, rolipram, gallein or M119 alone had no effect on LORR. Gallein (10 μM) significantly inhibited forskolin-stimulated cAMP accumulation in α2A-AR -CHO cells. Compared with Gβγ subunit inhibitors or DMED alone, [Ca2+]i and pERK1/2 was significantly increased after co-administration with Gβγ subunit inhibitors and DMED. DbcAMP (5 μM) or rolipram (5 μM) alone had no effect on ERK1/2 phosphorylation, but decreased DMED-induced ERK1/2 phosphorylation after co-administration with DMED. Gβγ subunit inhibitor treatment increased DMED-induced phosphorylation of CREB, whereas dbcAMP or rolipram had no effect on pCREB induced by DMED. From our results we conclude that, Gβγ subunit may inhibit DMED-induced sedation through the cAMP and pERK1/2 pathway.

journal_name

Eur J Pharmacol

journal_title

European journal of pharmacology

authors

Liu M,Yang Y,Tan B,Li Y,Zhou P,Su R

doi

10.1016/j.ejphar.2018.05.002

subject

Has Abstract

pub_date

2018-07-15 00:00:00

pages

28-37

eissn

0014-2999

issn

1879-0712

pii

S0014-2999(18)30258-9

journal_volume

831

pub_type

杂志文章

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