The odorant receptor OR2W3 on airway smooth muscle evokes bronchodilation via a cooperative chemosensory tradeoff between TMEM16A and CFTR
Jessie Huang, Hong Lam, Cynthia Koziol‐White, Nathachit Limjunyawong, Donghwa Kim, Nicholas Kim, N. Karmacharya, Premraj Rajkumar, Danielle Firer, Nicholas M. Dalesio, Joseph A. Jude, Richard C. Kurten, Jennifer L. Pluznick, Deepak A. Deshpande, Raymond B. Penn, Stephen B. Liggett, Reynold A. Panettieri, Xinzhong Dong, Steven S. An
Abstract
Significance Odorant sensing GPCRs are the largest gene family in the human genome. We previously found multiple olfactory receptors and their obligate downstream effectors expressed in the smooth muscle of human bronchi. However, the extent to which odorant-sensing receptors (and the ligands to which they respond) on airway smooth muscle (ASM) are physiologically relevant is not established. Here we show that a monoterpene nerol activates the odorant receptor OR2W3 to relax ASM in both cell and tissue models. Surprisingly, the mechanism of action of OR2W3-mediated ASM relaxation involves paradoxical increases in [Ca 2+ ] i that invoke a cooperative activation of TMEM16A and CFTR to compartmentalize calcium and regulate excitation-contraction coupling in human ASM cells.