Regulation of smooth muscle contractility is essential for many important biological processes such as tissue perfu- sion, blood pressure control, gastrointestinal motility and airway and bladder contraction. Smooth muscle cell tone is regulated by a variety of signalling mechanisms that are used by different neurotransmitters, hormones and auto- and paracrine substances. The two principal intracellular pathways for smooth muscle cell relaxation are believed to be activated by cGMP and cAMP. cGMP is generated by soluble guanylyl cyclase in response to NO (generated by the endothelium) or by particulate guanylyl cyclase in re- sponse to peptides such as atrial natriuretic peptide. Many other compounds activate receptors on the smooth muscle cell that couple via G s -proteins to adenylyl cyclase. This will lead to an increase in intracellular cAMP levels and a subsequent activation of cAMP-dependent protein kinase (PKA). Protein kinase A phosphorylation of myosin light chain kinase (MLCK) prevents the calcium-calmodulin complex from activating it. Furthermore, cAMP causes PKA-dependent phosphorylation of phospholamban, which increases Ca 2+ reuptake into the sarcoplasmic reticulum. This pathway has until now been seen as the classical path- way by which for instance β-adrenoceptor agonists, adeno- sine, histamine and prostacyclin induce relaxation of smooth muscle cells. This view has been substantiated by the fact that elevation of intracellular cAMP by the adenylyl cy- clase activator forskolin or phosphodiesterase inhibitors or administration of cell permeable cAMP analogues indeed lead to a pronounced relaxation of most smooth muscle cell types. In this issue of Naunyn-Schmiedeberg’s Archives of Pharmacology, Tanaka et al. (2003) show that besides cAMP-dependent mechanisms, also cAMP-independent signalling pathways are stimulated by G s -protein activa- tion in guinea pig airways that lead to relaxation of the tra- cheal smooth muscle. The authors have used cholera toxin, an activator of G s -proteins, to induce relaxation of tracheal smooth muscle. This relaxation was accompanied by an in- crease in cAMP content that was inhibited by the adenylyl cyclase inhibitor SQ22536. Surprisingly, SQ22536 had no influence on the cholera toxin-induced relaxation, indicat- ing a cAMP-independent relaxant mechanism. Interestingly, this communication doesn’t stand on its own, since increasing evidence demonstrates the existence of cAMP-independent mechanisms of smooth muscle cell relaxation. Apart from airway smooth muscle, existence of these cAMP-independent mechanisms has been shown in vascular and gastrointestinal smooth muscle cells for a variety of G s -coupled receptors, of which some examples are described below. In an early report Scornik et al. (1993) presented evidence that β-adrenoceptor-mediated activa- tion of coronary artery smooth muscle BK Ca potassium channels involves both PKA-dependent and -independent mechanisms. Upon reconstitution into lipid bilayers BK Ca channels were shown to be activated by isoprenaline, GTPγS, purified G sα and by the addition of the catalytic subunit of PKA. Inhibition of PKA activity prevented BK Ca channel stimulation by PKA, but not by endogenous G-protein or exogenous G sα , thus showing PKA-indepen- dency. Later it was shown that the dilation of coronary ar- terioles to adenosine is partly mediated by cAMP-inde- pendent mechanisms (Hein and Kuo 1999). Here the au- thors showed that Rp-8-Br-cAMPS, a cAMP antagonist, inhibited vasodilatation to the cAMP analogue 8-Br-cAMP but failed to block adenosine-induced dilatation. In another study by Turcato and Clapp (1999), SQ22536 had no in- fluence on the relaxation of phenylephrine pre-contracted isolated guinea pig aortae by iloprost. However, in the same study SQ22536 abolished the iloprost induced rise in cAMP, indicating that iloprost-induced vasodilatation is at least partly independent of cAMP levels. Similar results have been shown for beraprost-induced vasorelaxation in guinea-pig aorta (Yamaki et al. 2001). In rat mesenteric microvessels it was shown that the PKA inhibitors H7 and H89 failed to antagonise isoprenaline-induced vasodilata- Stephan L. M. Peters · Martin C. Michel cAMP-independent relaxation of smooth muscle cells via G s -coupled receptors Naunyn-Schmiedeberg’s Arch Pharmacol (2003) 368 : 329–330 DOI 10.1007/s00210-003-0816-2 Published online: 3 October 2003 EDITORIAL S. L. M. Peters (✉) · M. C. Michel Department Pharmacology and Pharmacotherapy, Academic Medical Centre, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands Tel.: +31-20-5667622, Fax: +31-20-6965976, e-mail: s.l.peters@amc.uva.nl © Springer-Verlag 2003