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The Journal of Neuroscience, May 27, 2009, 29(21):6809-6818; doi:10.1523/JNEUROSCI.5546-08.2009

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Cellular/Molecular
TMEM16B, A Novel Protein with Calcium-Dependent Chloride Channel Activity, Associates with a Presynaptic Protein Complex in Photoreceptor Terminals

Heidi Stöhr,¹ Julia B. Heisig,¹ Peter M. Benz,³ Simon Schöberl,² Vladimir M. Milenkovic,² Olaf Strauss,² Wendy M. Aartsen,⁴ Jan Wijnholds,⁴ Bernhard H. F. Weber,¹ and Heidi L. Schulz¹

¹Institut für Humangenetik, Universität Regensburg, and ²Experimentelle Ophthalmologie, Klinik und Poliklinik für Augenheilkunde, Klinikum der Universität Regensburg, 93053 Regensburg, Germany, ³Physiologisches Institut der Universität Würzburg, 97070 Würzburg, Germany, and ⁴Department of Neuromedical Genetics, The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands

Correspondence should be addressed to Dr. Heidi Stöhr, Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. Email: heidi.stoehr{at}klinik.uni-regensburg.de

Photoreceptor ribbon synapses release glutamate in response to graded changes in membrane potential evoked by vast, logarithmically scalable light intensities. Neurotransmitter release is modulated by intracellular calcium levels. Large Ca²⁺-dependent chloride currents are important regulators of synaptic transmission from photoreceptors to second-order neurons; the molecular basis underlying these currents is unclear. We cloned human and mouse TMEM16B, a member of the TMEM16 family of transmembrane proteins, and show that it is abundantly present in the photoreceptor synaptic terminals in mouse retina. TMEM16B colocalizes with adaptor proteins PSD95, VELI3, and MPP4 at the ribbon synapses and contains a consensus PDZ class I binding motif capable of interacting with PDZ domains of PSD95. Furthermore, TMEM16B is lost from photoreceptor membranes of MPP4-deficient mice. This suggests that TMEM16B is a novel component of a presynaptic protein complex recruited to specialized plasma membrane domains of photoreceptors. TMEM16B confers Ca²⁺-dependent chloride currents when overexpressed in mammalian cells as measured by halide sensitive fluorescent protein assays and whole-cell patch-clamp recordings. The compartmentalized localization and the electrophysiological properties suggest TMEM16B to be a strong candidate for the long sought-after Ca²⁺-dependent chloride channel in the photoreceptor synapse.

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Received Nov. 19, 2008; revised April 7, 2009; accepted April 20, 2009.

Correspondence should be addressed to Dr. Heidi Stöhr, Institute of Human Genetics, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. Email: heidi.stoehr{at}klinik.uni-regensburg.de

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