1990-1997 Undergraduate Studies in Physics and Economics - University of Hamburg, Germany
1995-2001 Graduate student and postdoctoral fellow at the Center for Molecular Neurobiology (ZMNH), Hamburg, Germany
2002-2008 Postdoctoral Fellow - University of California, San Francisco, USA
since 2009 Research Group Leader at the MDC
The last time you smelled a cookie and saliva was released into your mouth TMEM16A, a calcium activated chloride channel (CaCC), which was discovered recently, was involved. Its sequence is not related to any other ion channel or transporter and it is the founding member of a new protein family.
Calcium activated chloride currents have first been described in salamander photoreceptors in 1982, but the molecular identity remained an open problem until 2008. CaCCs are not only important for membrane potential stabilization in photoreceptors of the retina and the secretion of fluids in glands and airway epithelia They have also been implicated in a wide range of other physiological functions including the high-gain, low-noise amplification in olfactory transduction, taste adaptation, control of action potential waveform in neurons and positive feedback regulation of smooth muscle contraction induced by G protein-coupled receptors that is important to control vascular tone or uterus contraction.
Research in our laboratory focuses on the TMEM16 family of transmembrane proteins. The TMEM16 family has 10 members in mammals, 5 in fly and 1 in yeast. Beside the function of TMEM16A as CaCC little is known about this family. Mice containing a deletion in the TMEM16A gene die few weeks after birth and suffer from tracheomalacia, a development phenotype of the lung. Gnathodiaphyseal dysplasia, a rare disease characterized by bone fragility, sclerosis of tubular bones and lesions of the jawbone, is caused by mutations in the human TMEM16E gene. But the role of TMEM16E in healthy bone and how its disruption leads to the phenotype remain elusive. TMEM16J shows a very strong regulation by the tumor suppressor p53 and some TMEM16 proteins are highly amplified in specific forms of cancer.
Given the general role of chloride channels in mammalian physiology and the possibility that all TMEM16 proteins are involved in ion transport, we are interested in
- the biophysical functions / properties of TMEM16 proteins,
- the regulation and interaction partners of this proteins,
- the physiological function, in particular for sensory transduction, smooth muscle contraction and fluid secretion in epithelia,
- potential involvement in human inherited diseases.
To understand the properties of the various members of this protein family we use a large variety of techniques including single-cell fluorescence imaging and electrophysiology in cellular and animal models.
We are also interested in the interplay between TMEM16A and the cystic fibrosis conductance regulator (CFTR), a chloride channel whose defect causes cystic fibrosis in humans. In airway epithelia CaCCs are colocalized with CFTR. However CFTR knock out mice do not show the lung phenotype, which is the most severe complication in humans suffering from this disease. Mice do express far more CaCC in lung than humans and it is believed that in the animals the CaCCs compensate the lost function of CFTR. Finding a way to increase the open probability of TMEM16A channels using drugs might also help to bypass the defect CFTR channel in human patients.
We hope that our research will help to develop new treatments for diseases like hypertension, asthma, chronic pain and cystic fibrosis.
Schroeder BC, Cheng T, Jan Y, Jan LY, (2008). Expression cloning of TMEM16A as a calcium activated chloride channel subunit. Cell, 134, 1019-1029.
Hartzell HC, Yu k, Xiao Q, Chien LT, Qu Z, (2008). Anoctamin / TMEM16 family members are Ca2+ activated Cl- channels. J Physiol [Epub ahead of print] (review)
Hartzell C, Putzier I, Arreola J (2005), Calcium activated chloride channels. Annu Rev Physiol, 67, 719-758. (review).
Schroeder BC, Cheng T, Jan Y, Jan LY, (2008). Expression cloning of TMEM16A as a calciumactivated chloride channel subunit. Cell, 134, 1019-1029.
Estévez R*, Schroeder BC*, Accardi A, Jentsch TJ, Pusch M., (2003). Conservation of chloride channel structure revealed by an inhibitor binding site in ClC-1. Neuron, 38, 47-59.
Schroeder BC*, Waldegger S*, Fehr S, Bleich M, Warth R, Greger R, Jentsch TJ., (2000). A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature, 403, 196-9.
Kubisch C*, Schroeder BC*, Friedrich T, Lutjohann B, El-Amraoui A, Marlin S, Petit C, Jentsch TJ., (1999). KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell, 96, 437-46.
Schroeder BC*, Kubisch C*, Stein V, Jentsch TJ., (1998). Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy. Nature, 396, 687-90.
Biervert C*, Schroeder BC*, Kubisch C, Berkovic SF, Propping P, Jentsch TJ, Steinlein OK., (1998). A potassium channel mutation in neonatal human epilepsy. Science, 279, 403-6.
*: contributed equally