Olfactory Receptors Modulate Physiological Processes in Human Airway Smooth Muscle Cells

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.

Functional expression of olfactory receptors in human primary melanoma and melanoma metastasis

“…However, the physiological role of these human ORs has only been characterized in a few examples of healthy tissues such as skin and in pathophysiologically altered tissues such as prostate tumor . The few studies investigating the function of ORs in healthy tissues demonstrate that ORs are involved in the secretion processes of cytokines and hormones by airway smooth muscle cells, enterochromaffin cells and keratinocytes; in chemotaxis and acrosome reaction of sperm, the muscle contraction as well as in processes of cell migration and proliferation …”

Functional characterization of the extranasal OR2A4/7 expressed in human melanocytes

“…It is well known that cAMP as a second messenger is capable of activating diverse effector molecules, such as ion channels that permit the influx of Ca 2+ from the extracellular space into the cell. Transient Ca 2+ signals could commonly be generated in the course of OR activation in distinct cell types, but the Ca 2+ responses differ in their kinetics . When comparing CHS and β‐ionone‐induced calcium responses in melanocytes, there are differences concerning the threshold concentration to trigger significant cellular signals, the EC 50 values (~254 μmol/L for CHS and ~60 μmol/L for β‐ionone) and the time to peak (25 minutes for CHS and 5‐10 minutes for β‐ionone).…”

“…Meanwhile, the physiological function of some extranasal ORs has also been characterized . These ORs are thought to serve for the regulation of cellular processes in, for example, human spermatozoa, pancreas, heart or human airway smooth muscle cells . Furthermore, ORs have been detected in cancer tissues as well as cell lines and have exhibited an involvement in the processes of proliferation, migration and apoptosis …”

“…In any case, an odourant‐stimulated signal transduction cascade is initiated through a heterotrimeric G s protein, whereupon the intracellular release of “classic” second messengers, cyclic AMP (cAMP) and calcium (Ca 2+ ), become apparent. The activation of a cAMP‐dependent protein kinase A (PKA) is henceforth rendered possible, whereas other receptor‐associated signalling cascades include phospholipase C (PLC) or phosphoinositide‐3‐kinase (PI3K) . Further downstream signalling components encompass mitogen‐activated protein kinases (MAPKs) that are supposed to alter the intracellular physiology …”

Von riechenden Zellen

“…"Amylbutyrat könnte bei Asthma helfen, die Luftzufuhr zu verbessern", folgert Prof. Dr. Hatt. "Vermutlich kann es nicht nur den Effekten von Histamin entgegenwirken, sondern ebenso denen von anderen Allergenen, die das Atmen behindern" [1]. Auch für die Behandlung anderer Krankheiten, etwa der chronisch obstruktiven Lungenerkrankung, könne der Rezeptor interessant sein.…”