Adrenaline (ADR) and noradrenaline (NA) can simultaneously activate inhibitory α2‐ and stimulatory β‐adrenoceptors (AR). However, ADR and NA differ significantly in that ADR is a potent β2‐AR agonist while NA is not. Only recently has the interaction resulting from the simultaneous activation of α2‐ and β2‐AR been examined at the cellular level to determine the mechanisms of α2‐AR regulation following concomitant activation of both α2‐ and β2‐ARs by chronic ADR. This study evaluates β2‐AR regulation of α2A‐AR signalling following chronic ADR (300 nM) and NA (1 and 30 μM) treatments of BE(2)‐C human neuroblastoma cells that natively express both β2‐ and α2A‐ARs. Chronic (24 h) treatment with ADR (300 nM) desensitized the response to the α2A‐AR agonist, brimonidine, in BE(2)‐C cells. Addition of the β‐AR antagonist, propranolol, blocked the ADR‐induced α2A‐AR desensitization. Unlike ADR, chronic NA (1 μM) treatment had no effect on the α2A‐AR response. However if NA was increased to 30 μM for 24 h, α2A‐AR desensitization was observed; this desensitization was partially reversed by propranolol. Chronic ADR (300 nM) treatment reduced α2A‐AR binding levels, contributing to the α2A‐AR desensitization. This decrease was prevented by addition of propranolol during ADR treatment. Chronic NA (30 μM), like ADR, treatment lowered specific binding, whereas 1 μM 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 α2A‐AR desensitization and down‐regulation. Acute (1 h) ADR (300 nM) or NA treatment (1 μM) produced α2A‐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 α2A‐AR desensitization by mechanisms that involve up‐regulation of GRK3 and down‐regulation of α2A‐AR levels through interactions with the β2‐AR. British Journal of Pharmacology (2003) 138, 921–931. doi:

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