β-Adrenoceptors, cAMP and airway smooth muscle relaxation: challenges to the dogma

β-Adrenoceptor agonists are assumed to induce airway smooth muscle relaxation through the cAMP-protein kinase A (PKA) phosphorylation cascade system. This traditional second messenger paradigm of β-adrenoceptor agonist action is deeply engrained, but in this article Theodore Torphy reviews recent observations that force a re-examination of the dogma. For example, cAMP can activate protein kinase G as well as PKA, and this unanticipated dual action may contribute to the relaxant activity of cAMP. Other studies suggest that β-adrenoceptor agonists can induce relaxation by a cAMP-independent mechanism involving a direct coupling of the β-adrenoceptor to Ca 2+-dependent K+ channels. Consequently, it is possible that multiple cAMP-dependent pathways act in concert with cAMP-independent pathways to mediate bronchodilation in response to β-adrenoceptor agonists.