β2-Adrenoceptor (β2-AR) agonists increase skeletal muscle contractile force via activation of Gs protein/adenylyl cyclases and increased generation of cAMP. Duarte et al. evaluated the possible dual coupling of β2-AR to Gs and Gi proteins and the influence of β2-AR/Gs-Gi/cAMP signaling cascade on skeletal muscle contraction. Clenbuterol/fenoterol, forskolin, and rolipram induced transient positive inotropic effects. The late descending phase of β2-AR agonist inotropic effect was mimicked by either cAMP or adenosine and abolished by pertussis toxin (PTX) (Gi signaling inhibitor) or the organic anion transporter inhibitor probenecid, indicating a delayed coupling of β2-AR to Gi protein, which depends on cAMP efflux. Remarkably, the PTX-sensitive β2-AR inotropic effect was inhibited by the A1 adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine and ecto-5′-phosphodiesterase inhibitor α,β-methyleneadenosine 5′-diphosphate sodium salt, indicating that β2-AR coupling to Gi is indirect and dependent on A1 receptor activation. These studies suggest that the extracellular cAMP-adenosine pathway may represent a general autocrine and/or paracrine mechanism that indirectly modulates the signaling triggered by distinct receptors coupled to Gs proteins, qualifying cyclic nucleotides as extracellular third messengers and the extracellular cAMP-adenosine signaling pathway as potential pharmacological targets for therapeutic intervention.
See article at J Pharmacol Exp Ther 2012, 341:820–828.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics