TMEM16a and Cystic Fibrosis

A 2014 review from the Galietta lab (PMID: 24704530) explores the link between CFTR and TMEM16a and how these details could lead to new pathways for treatment of Cystic Fibrosis.

            Worldwide, more than 70,000 people struggle to breathe due to a chronic genetic disease known as Cystic Fibrosis (CF). CF is caused one of 1,700 mutations in a Cl- channel called CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) which alter the ability of the channel to pass Cl- ions into the mucus that lines the lungs. Typically, CFTR mediated Cl- flux is required for thin and healthy mucus. In CF patients, this mucous thickens, and is prone frequent airway infections, and decreased absorption of nutrients during digestion1 and these patients have trouble breathing. Many of the symptoms of CF are direct effects of decreased mucosal clearance and the buildup of thick, sticky mucous that occurs. Interestingly, our favorite channel, TMEM16a passes Cl- in the same cell types as CFTR.

TMEM16A is not defective in the tissues of CF patients. TMEM16A is a Ca2+-activated Cl- channel and has a similar thinning effect on mucous to functional CFTR. The channel is also permeable to bicarbonate (HCO3-), a compound that supports mucous expansion and has antimicrobial effects. So, should Cl- and HCO3- secretion through TMEM16A be triggered, thick mucosal buildup due to CFTR dysfunction could be rescued. Because CFTR mutations can be varied in CF patients, treatment targeting CFTR must be patient-specific. However, treatments targeting TMEM16A would be genotype-blind and would not have to vary patient-to-patient.

            TMEM16a wasn’t identified as the Ca2+-activated Cl- channel in airway cells until 2008. Even so, before the identity of TMEM16a was known, teams recognized the promise of targeting an airway Cl- channel with a different activation mechanism than CFTR. So, they tested therapies targeting general Ca2+-activated Cl- in airway cells. These trials didn’t show proof of respiratory improvement, but, the compound used had a very short half-life in the respiratory system and did not target TMEM16A specifically. It is possible that more specifically designed compounds would show more promising results in treating CF. Such compounds could be designed to activate TMEM16A, inhibit removal of TMEM16A from the membrane, or inhibit desensitization to TMEM16A activity. The current debate in the field is actually whether down regulation, rather than upregulation of TMEM16a is a better strategy. There has been some evidence that inhibition of the channel can block mucous secretion, which would be another strategy to prevent and treat mucous buildup. However, a more recent study by Sonneville et al. (PMCID 28955034) suggests that downregulation of TMEM16A (therein referred to as ANO1) contributes to CFTR pathology.

Moving forward, recent studies (notably Paulino et al., 2017; PMID: 29236691) have given us more information on the structure of the TMEM16A, which can greatly help in the drug-design process. However, there is still little information available about the regulation of TMEM16A activity and what other cellular molecules the channel interacts with. Every piece of information we gather may bring us closer to a treatment for CF. Who could have known how many important jobs this orphan channel could do! 


Post written by Rachel Bainbridge & Anne Carlson


Anne Carlson