Cyclic nucleotide-gated (CNG) channels are important mediators in the transduction pathways of rod and cone photoreceptors. Native CNG channels are heterotetramers composed of homologous A and B subunits. In heterologous expression systems, B subunits alone cannot form functional CNG channels, but they confer a number of channel properties when coexpressed with A subunits. To investigate the importance of the CNGB subunits in vivo, we deleted the CNGB1 gene in mice. In the absence of CNGB1, only trace amounts of the CNGA1 subunit were found on the rod outer segment. As a consequence, the vast majority of isolated rod photoreceptors in mice lacking CNGB1 (CNGB1 Ϫ/Ϫ ) failed to respond to light. In electroretinograms (ERGs), CNGB1 Ϫ/Ϫ mice showed no rod-mediated responses. The rods also showed a slow-progressing degeneration caused by apoptotic death and concurred by retinal gliosis. Cones were primarily unaffected and showed normal ERG responses up to 6 months, but they started to degenerate in later stages. At the age of ϳ1 year, CNGB1 Ϫ/Ϫ animals were devoid of both rods and cones. Our results show that CNGB1 is a crucial determinant of native CNG channel targeting. As a result of the lack of rod CNG channels, CNGB1 Ϫ/Ϫ mice develop a retinal degeneration that resembles human retinitis pigmentosa.

The loss of CNGA3 impairs the targeting of cone opsins and the expression of other visual cascade proteins. In addition, CNGA3 appears to be essential for normal postnatal migration of cone somata. After loss of cone outer segment proteins, CNGA3(-/-) cones induce apoptotic cell death.

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 Ca 2؉ -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. Cyclic nucleotide-gated (CNG)3 channels are molecular switches converting receptor-mediated increases in cytosolic concentrations of cAMP or cGMP into an influx of cations. The channels play a key role in visual and olfactory transductions. The CNG channel involved in olfaction is expressed at high density in the sensory cilia of olfactory receptor neurons (ORNs) where it is activated by an odorant-induced rise of cAMP. When open, the channel conducts mainly Ca 2ϩ and Na ϩ (1, 2). The subsequent rise in internal Ca 2ϩ