Beta-adrenoceptors, cAMP and airway smooth muscle relaxation: challenges to the dogma.
beta-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 beta-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 beta-adrenoceptor agonists can induce relaxation by a cAMP-independent mechanism involving a direct coupling of the beta-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 beta-adrenoceptor agonists.
Torphy
T J
TJ
Department of Inflammation and Respiratory Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D009126:Muscle Relaxation; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015290:Second Messenger Systems
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases