Does coupling to ADP ribosylation factor 6 explain differences between muscarinic and other receptors in interaction with β-adrenoceptor-mediated smooth muscle relaxation?

Abstract

Numerous studies in airways, ileum, and urinary bladder have demonstrated that relaxation by β-adrenoceptor agonists has lower potency and/or efficacy when contraction was elicited by muscarinic receptor agonists as compared to other G-protein-coupled receptors, KCl, or basal tone, but the molecular mechanisms behind this relative resistance remain unclear. A paper by Huang et al. in this issue demonstrates that NAV2729, an inhibitor of ADP ribosylation factor 6, inhibits contraction of isolated blood vessels elicited by muscarinic receptor agonists, but not by α₁-adrenoceptor agonists or KCl. Against this background, we discuss the role of ADP ribosylation factor 6 in cellular responses to G-protein-coupled receptor stimulation. While ADP ribosylation factor 6 apparently is the only promising molecular explanation for the relative resistance of smooth muscle contraction elicited by muscarinic agonists, the existing data are insufficient for a robust conclusion.

Keywords: ADP ribosylation factor 6; Contraction; G-Protein-coupled receptor; Muscarinic receptor; β-Adrenoceptor.

Fig. 1

Schematic drawing of ARF6-mediated cellular effects in GPCRs agonist stimulation. Dashed red arrow, negative regulatory effect; black arrow, positive regulatory effect; GAP, GTPase-activating proteins; GDP, guanosine diphosphate; GEF, guanine nucleotide exchange factors; GTP, guanosine triphosphate; ↑, increase; ↓, decrease; ↔ , no effect