title: Loss of CNGB1 protein leads to olfactory dysfunction and subciliary cyclic nucleotide-gated channel trapping.
abstract: 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.
authors.affiliation: Department Pharmazie, Zentrum für Pharmaforschung, Ludwig-Maximilians Universitüt München, D-81377 München, Germany.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
authors.forename: Johannes
authors.initials: J
authors.lastname: Reisert
authors.forename: Heidi
authors.initials: H
authors.lastname: Geiger
authors.forename: Christian
authors.initials: C
authors.lastname: Wetzel
authors.forename: Xiangang
authors.initials: X
authors.lastname: Zong
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bradley
authors.forename: Marc
authors.initials: M
authors.lastname: Spehr
authors.forename: Sabine
authors.initials: S
authors.lastname: Hüttl
authors.forename: Andrea
authors.initials: A
authors.lastname: Gerstner
authors.forename: Alexander
authors.initials: A
authors.lastname: Pfeifer
authors.forename: Hanns
authors.initials: H
authors.lastname: Hatt
authors.forename: King-Wai
authors.initials: KW
authors.lastname: Yau
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
mesh_terms: D000818:Animals; D001835:Body Weight; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels; D005260:Female; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009711:Nucleotides / Q000378:metabolism*; D009830:Olfactory Bulb / Q000378:metabolism*
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D007473:Ion Channels; D009711:Nucleotides; D017871:Calcium-Calmodulin-Dependent Protein Kinases