Interdicting Gq Activation in Airway Disease by Receptor-Dependent and Receptor-Independent Mechanisms

G alpha(q)beta gamma heterotrimer (G(q)), an important mediator in the pathology of airway disease, plays a central role in bronchoconstriction and airway remodeling, including airway smooth muscle growth and inflammation. Current therapeutic strategies to treat airway disease include the use of muscarinic and leukotriene receptor antagonists; however, these pharmaceuticals demonstrate a limited clinical efficacy as multiple G(q)-coupled receptor subtypes contribute to these pathologies. Thus, broadly inhibiting the activation of G(q) may be an advantageous therapeutic approach. Here, we investigated the effects of broadly inhibiting G(q) activation in vitro and ex vivo using receptor-dependent and receptor-independent strategies. P4pal-10 is a protease activated receptor 4-derived pepducin that exhibits efficacy toward multiple G(q)-coupled receptors. Mechanistic studies demonstrated that P4pal-10 selectively inhibits all G protein coupling to several G(q)-coupled receptors, including protease activated receptor 1, muscarinic acetylcholine M3, and histamine H1 receptors, while demonstrating no direct effect on G(q). We also evaluated the ability of FR900359, also known as UBO-QIC, to directly inhibit G(q) activation. FR900359 inhibited spontaneous G alpha(q) nucleotide exchange, while having little effect on G alpha(s)beta gamma, G alpha(i)beta gamma, or G alpha(12/13)beta gamma heterotrimer activity. Both P4pal-10 and FR900359 inhibited G(q)-mediated intracellular signaling and primary human airway smooth muscle growth, whereas only FR900359 effectively interdicted agonist-promoted airway contraction in human precision cut lung slices. These studies serve as a proof of concept that the broad-based inhibition of G(q) activation may be a useful therapeutic approach to treat multiple common pathologies of airway disease.