Penalties for Sexual Offences

Abstract

G<i>α</i>_q<i>βγ</i> 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<i>α</i>_q nucleotide exchange, while having little effect on G<i>α</i>_s<i>βγ</i>, G<i>α</i>_i<i>βγ</i>, or G<i>α</i>_12/13<i>βγ</i> 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.