Abstract
The CaSR plays an integral role in the regulation of parathyroid hormone (Pth) and is widely expressed in the epithelium of the developing lung (J Physiol 586:2008). Recently, Lambrecht et al. reported CaSR is expressed on the cells of neuroepithelial bodies (NEB) in the post-natal lung (J Cell Sci 126:2013). NEB are proposed to act as both hypoxia sensors and mechanosensors; however, while in vitro and morphological evidence supports both roles, neither hypothesis has been functionally addressed in vivo. We employed a double-knockout (CaSR-/-, Pth-/-; KO) mouse model to examine the impact of loss of CaSR on pulmonary mechano- and chemo- sensation, as assessed via action potential discharge in single, vagal, slowly-adapting receptors (SAR) during quasi-static inflation in hyperoxic (40% O2-, 60% N2) and hypoxic (10% O2, 90%N2) conditions. Hypoxia did not alter the discharge frequency (f) vs tracheal pressure (Ptr) relationship in wildtype (WT; n = 7) or CaSR- KO (n= 7) mice (P > 0.05). In normoxia, KO mice exhibited decreased f compared with WT mice (P = 0.001, 2-way ANOVA; mean + SEM: Ptr=5cmH2O: WT, 86+9.3 vs KO, 74+7.1; 10cmH2O: 148+10.7 vs 111+8.2; 15cmH2O: 191+18.8 vs 124+9.1; 20cmH2O:150+40.7 vs 116+8.6). During hypoxia, KO mice showed a similarly reduced f vs Ptr relationship vs the WT (P<0.001). We conclude that hypoxia does not alter murine SAR mechanosensitivity whereas, loss of CaSR function reduces SAR mechanosensitivity. We identify a novel mechanism involved in SAR mechanosensitivity to lung inflation relevant to the physiology of pulmonary sensation and respiratory phenotypes of individuals exhibiting CaSR mutations.
- © 2014 ERS