Numerous potentially harmful particles constantly enter our lungs. To guard against this, they are lined with a physical barrier called airway epithelium. In the conducting airways, this pseudostratified layer consists predominantly of mucus secreting goblet cells and ciliated cells. Their joint function is to trap and physically propel these particles out of the lung-a tightly regulated innate defence mechanism known as mucociliary clearance (MCC) 1.
Ciliated cells play a dual role in this process via ciliary beating and ion transport. The former is based on a coordinated wave-like motion of cilia. These are located on the apical membrane of the cell, layered by the periciliary liquid (PCL), which hydrates the airways and enables their smooth movement. Formation of PCL is a result of the water movement from serosa onto the apical surface through the tight junctions and is mediated by ion flow across the epithelium (Fig.1). A defect in this hydration mechanism results in conditions such as asthma, cystic fibrosis and chronic obstructive pulmonary disease1.
Figure 1. Ion transport hydration model in airway epithelium (Hollenhorst, 2011)
Currently, one of the main therapeutic targets is the ion channel TMEM16A, a member of Calcium Activated Chloride Channel family (CaCC). In the lung, upregulation of its Cl– and HCO3– secretion would promote PCL formation and re-establish airway homeostasis2. However, it has been demonstrated that a family of goblet-cell-derived proteins, known as Calcium-activated chloride channel regulators (CLCA), can regulate CaCC-mediated chloride currents. Chloride channel accessory 1 (CLCA1), one of the family members, and TMEM16A were found to be upregulated in response to inflammatory mediators, especially in conditions such as asthma and COPD, where they contribute to excessive mucus production3.
However, a recently published study by Sala-Rabanal et al. (2015) was the first to functionally link the two proteins, and specifically identify CLCA1 as a secreted modifier of TMEM16A. The hypothesis is that this effector protein acts in a paracrine fashion and exerts its effect via stabilising the TMEM16A channel dimer on the cell surface. As a result, it increases its surface expression and potentially elevates calcium dependent chloride currents, which could therefore increase MCC (Fig.2)4.
This makes both the CLCA1 and its site of interaction with TMEM16A, promising, and perhaps optimal, therapeutic targets for chronic obstructive airway diseases. Especially, since very few of the molecular players involved in mucus overproduction, driven by mucous cell metaplasia (MCM), have been identified so far5. Nevertheless, much more information will be required regarding the CLCA1-TMEM16A structure and interaction, within the MCC and MCM pathway.
Figure 2. Proposed mechanism of CLCA1-TMEM16A inter-/action (Sala-Rabanal, 2015)
Blog by Karin Smrekar
- Hollenhorst, M. I., Richter, K., Fronius, M. (2011). Ion Transport by Pulmonary Epithelia. Journal of Biomedicine and Biotechnology, 2011.
- Caputo, A., Caci, E., Ferrera, L., Pedemonte, N., Barsanti, C., Sondo, E., Pfeffer, U., Ravazzolo, R., Zeagara-Moran, O., Galietta, L.J.. (2008). TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science, 590-594.
- Alevy, Y.G., Patel, A.C., Romero, A.G., Patel,D.A., Tucker, J., Roswit, W.T., Miller, C.A., Heier, R.F., Byers, D.E., Brett, T.J., Holtzman, M.J. (2012), IL-13–induced airway mucus production is attenuated by MAPK13 inhibition. The Journal of Clinical Investigation, 122 (2); 4555-4568.
- Sala-Rabanal, M., Yurtsever, Z., Nichols, C.G., Brett, T.J. (2015). Secreted CLC1 modulates TMEM16A to activate Ca2+ -dependent chloride currents in human cells. eLife.
- Brett, T.J. (2015). CLCA1 and TMEM16A: the link towards a potential cure for airway diseases. Expert Review of Respiratory Medicine, 503-506.