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J. Biol. Chem., Vol. 281, Issue 46, 35156-35166, November 17, 2006

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Loss of CNGB1 Protein Leads to Olfactory Dysfunction and Subciliary Cyclic Nucleotide-gated Channel Trapping^*

Stylianos Michalakis¹, Johannes Reisert^*, Heidi Geiger, Christian Wetzel^¶, Xiangang Zong, Jonathan Bradley, Marc Spehr^¶, Sabine Hüttl, Andrea Gerstner, Alexander Pfeifer, Hanns Hatt^¶, King-Wai Yau, and Martin Biel²

From the Department Pharmazie, Zentrum für Pharmaforschung, Ludwig-Maximilians Universitüt München, D-81377 München, Germany, the Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and the ^¶Lehrstuhl für Zellphysiologie, Ruhr-Universitüt Bochum, D-44780 Bochum, Germany

Olfactory receptor neurons (ORNs) employ a cyclic nucleotide-gated (CNG) channel to generate a receptor current in response to an odorant-induced rise in cAMP. This channel contains three types of subunits, the principal CNGA2 subunit and two modulatory subunits (CNGA4 and CNGB1b). Here, we have analyzed the functional relevance of CNGB1 for olfaction by gene targeting in mice. Electro-olfactogram responses of CNGB1-deficient (CNGB1^-/-) mice displayed a reduced maximal amplitude and decelerated onset and recovery kinetics compared with wild-type mice. In a behavioral test, CNGB1^-/- mice exhibited a profoundly decreased olfactory performance. Electrophysiological recordings revealed that ORNs of CNGB1^-/- mice weakly expressed a CNG current with decreased cAMP sensitivity, very rapid flicker-gating behavior and no fast modulation by Ca²⁺-calmodulin. Co-immunoprecipitation confirmed the presence of a CNGA2/CNGA4 channel in the olfactory epithelium of CNGB1^-/- mice. This CNGA2/CNGA4 channel was targeted to the plasma membrane of olfactory knobs, but failed to be trafficked into olfactory cilia. Interestingly, we observed a similar trafficking defect in mice deficient for the CNGA4 subunit. In conclusion, these results demonstrate that CNGB1 has a dual function in vivo. First, it endows the olfactory CNG channel with a variety of biophysical properties tailored to the specific requirements of olfactory transduction. Second, together with the CNGA4 subunit, CNGB1 is needed for ciliary targeting of the olfactory CNG channel.

Received for publication, July 5, 2006 , and in revised form, September 14, 2006.

^* This work was supported in part by the Deutsche Forschungsgemeinschaft (to M. B. and A. G.) and Grant DC06904 from the National Institutes of Health (to K.-W. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. Pharmazie, Pharmakologie für Naturwissenschaften, Ludwig-Maximilians-Universitüt München, Butenandtstr. 7, D-81377 München, Germany. Tel.: 49-89-2180-77327; Fax: 49-89-2180-77326; E-mail: mbiel{at}cup.uni-muenchen.de.

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