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Desensitization of α 2A ‐adrenoceptor signalling by modest levels of adrenaline is facilitated by β 2 ‐adrenoceptor‐dependent GRK3 up‐regulation
Author(s) -
Bawa Tasneem,
Altememi Ghazi F,
Eikenburg Douglas C,
Standifer Kelly M
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705127
Subject(s) - desensitization (medicine) , propranolol , alpha (finance) , agonist , antagonist , endocrinology , medicine , chemistry , beta (programming language) , isoprenaline , receptor , pharmacology , stimulation , construct validity , nursing , computer science , patient satisfaction , programming language
Adrenaline (ADR) and noradrenaline (NA) can simultaneously activate inhibitory α 2 ‐ and stimulatory β‐adrenoceptors (AR). However, ADR and NA differ significantly in that ADR is a potent β 2 ‐AR agonist while NA is not. Only recently has the interaction resulting from the simultaneous activation of α 2 ‐ and β 2 ‐AR been examined at the cellular level to determine the mechanisms of α 2 ‐AR regulation following concomitant activation of both α 2 ‐ and β 2 ‐ARs by chronic ADR. This study evaluates β 2 ‐AR regulation of α 2A ‐AR signalling following chronic ADR (300 n M ) and NA (1 and 30 μ M ) treatments of BE(2)‐C human neuroblastoma cells that natively express both β 2 ‐ and α 2A ‐ARs. Chronic (24 h) treatment with ADR (300 n M ) desensitized the response to the α 2A ‐AR agonist, brimonidine, in BE(2)‐C cells. Addition of the β‐AR antagonist, propranolol, blocked the ADR‐induced α 2A ‐AR desensitization. Unlike ADR, chronic NA (1 μ M ) treatment had no effect on the α 2A ‐AR response. However if NA was increased to 30 μ M for 24 h, α 2A ‐AR desensitization was observed; this desensitization was partially reversed by propranolol. Chronic ADR (300 n M ) treatment reduced α 2A ‐AR binding levels, contributing to the α 2A ‐AR desensitization. This decrease was prevented by addition of propranolol during ADR treatment. Chronic NA (30 μ M ), like ADR, treatment lowered specific binding, whereas 1 μ M NA treatment was without effect. Chronic ADR treatment produced a significant increase in GRK3 levels and this was blocked by propranolol or GRK2/3 antisense DNA treatment. This antisense DNA, common to both GRK2 and GRK3, also blocked chronic ADR‐induced α 2A ‐AR desensitization and down‐regulation. Acute (1 h) ADR (300 n M ) or NA treatment (1 μ M ) produced α 2A ‐AR desensitization. The desensitization produced by acute treatment was β‐AR independent, as it was not blocked by propranolol. We conclude that chronic treatment with modest levels of ADR produces α 2A ‐AR desensitization by mechanisms that involve up‐regulation of GRK3 and down‐regulation of α 2A ‐AR levels through interactions with the β 2 ‐AR.British Journal of Pharmacology (2003) 138 , 921–931. doi: 10.1038/sj.bjp.0705127