Research Report 2010 - MDC

CaCC in olfactory receptor neurones Binding of odorants to specific G-protein coupled receptors activates an adenylate cyclase (AC) through theG-protein β-subunit Golf. The produced cAMP binds to and opens cyclic nucleotide gated channels and calcium enters the cell. The initial depolarizationcaused by the opening of this unselective cation channels is than amplified by the opening of CaCCs. It has been estimated that the chloridecurrent can be up to 30 times larger than the cation current.We generated antibodies against TMEM16A and othermembers of the family and could show that TMEM16Aand F show highly polarized expression in epithelialcells and some neurons. This is consistent with calciumactivated chloride currents in native cells which displayin an asymmetric fashion.TMEM16 in vivo studiesTo understand the in vivo function of TMEM16 proteinsand their relationship to CaCCs we, in collaborationwith the group of Christian Hübner, University of Jena,have started to generate TMEM16 knock out mice. To dothis we have used floxed constructs. This will give usthe option of a tissue specific knock out by crossing thefloxed lines with appropriate Cre lines. Currently, it isonly possible to speculate about the experiments necessaryfor the analysis as they will depend mainly onthe observed phenotypes. For the analysis we plan totest physiological functions known or hypothesized todepend on CaCCs including olfaction, taste and bloodpressure regulation. In addition we are interested in therole of TMEM16A in transepithelial water- and iontransport of the lung. Its expression in airway epitheliamakes it a good candidate to be the channel that couldbypass the defective CFTR chloride channel in patientssuffering from cystic fibrosis.We hope that our research will not only help to understandthe physiological role of CaCCs, but also lead tonew treatments of diseases like hypertension, asthmaor cystic fibrosis.Selected PublicationSchroeder, BC, Cheng, T, Jan, YN, Jan, LY. (2008). Expression cloning ofTMEM16A as a calcium-activated chloride channel subunit. Cell. 134,1019-1029.Function and Dysfunction of the Nervous System 171