Abstract
Pathophysiological mechanisms in human airway smooth muscle cells (HASMCs) significantly contribute to the progression of chronic inflammatory airway diseases with limited therapeutic options, such as severe asthma and COPD. These abnormalities include the contractility and hyperproduction of inflammatory proteins. To develop therapeutic strategies, key pathological mechanisms, and putative clinical targets need to be identified. In the present study, we demonstrated that the human olfactory receptors (ORs) OR1D2 and OR2AG1 are expressed at the RNA and protein levels in HASMCs. Using fluorometric calcium imaging, specific agonists for OR2AG1 and OR1D2 were identified to trigger transient Ca2+ increases in HASMCs via a cAMP-dependent signal transduction cascade. Furthermore, the activation of OR2AG1 via amyl butyrate inhibited the histamine-induced contraction of HASMCs, whereas the stimulation of OR1D2 with bourgeonal led to an increase in cell contractility. In addition, OR1D2 activation induced the secretion of IL-8 and GM-CSF. Both effects were inhibited by the specific OR1D2 antagonist undecanal. We herein provide the first evidence to show that ORs are functionally expressed in HASMCs and regulate pathophysiological processes. Therefore, ORs might be new therapeutic targets for these diseases, and blocking ORs could be an auspicious strategy for the treatment of early-stage chronic inflammatory lung diseases.
Highlights
Olfactory receptors (ORs) represent the largest supergene family within the class of G proteincoupled receptors (GPCRs)
We first aimed to characterize the odor-dependent activation of human airway smooth muscle cells (HASMCs)
Because OR activation leads to a Ca2+ influx in OR neurons and Ca2+ initiates the contraction of HASMCs, we investigated the intracellular Ca2+ levels after receptor activation using fluorometric calcium imaging
Summary
Olfactory receptors (ORs) represent the largest supergene family within the class of G proteincoupled receptors (GPCRs). They detect volatile odorant molecules by specific binding. A heterotrimeric G protein (Golf) is activated (Jones and Reed, 1989; Belluscio et al, 1998), stimulating an adenylyl cyclase III (ACIII), which in turn generates cyclic adenosine monophosphate (cAMP; Bakalyar and Reed, 1990) This process leads to an opening of cyclic nucleotide-gated (CNG) channels, which conduct Ca2+ ions to the intracellular space, resulting in a depolarization of the OSN (Dhallan et al, 1990; Bradley et al, 1994). In non-chemosensory tissues, parts of this canonical pathway have been identified, but alternative signal transduction components have been described (Spehr et al, 2011; Busse et al, 2014; Maßberg et al, 2015)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
