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The Journal of Neuroscience, January 5, 2005, 25(1):130-138; doi:10.1523/JNEUROSCI.3764-04.2005

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Cellular/Molecular
Impaired Channel Targeting and Retinal Degeneration in Mice Lacking the Cyclic Nucleotide-Gated Channel Subunit CNGB1

Sabine Hüttl,¹ Stylianos Michalakis,¹ Mathias Seeliger,^2 * Dong-Gen Luo,^3 * Niyazi Acar,² Heidi Geiger,¹ Kristiane Hudl,² Robert Mader,¹ Silke Haverkamp,⁴ Markus Moser,⁵ Alexander Pfeifer,¹ Andrea Gerstner,¹ King-Wai Yau,³ and Martin Biel¹

¹Department Pharmazie, Pharmakologie für Naturwissenschaften, Ludwig-Maximilians-Universität München, D-81377 München, Germany, ²Retinal Electrodiagnostics Research Group, Universitäts-Augenklinik Tübingen, D-72076 Tübingen, Germany, ³Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, ⁴Department of Neuroanatomy, Max-Planck-Institute for Brain Research, D-60528 Frankfurt/Main, Germany, and ⁵Department of Molecular Medicine, Max-Planck-Institute of Biochemistry, D-82152 Martinsried, Germany

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^-/-) failed to respond to light. In electroretinograms (ERGs), CNGB1^-/- 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 1 year, CNGB1^-/- 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^-/- mice develop a retinal degeneration that resembles human retinitis pigmentosa.

Key words: cyclic nucleotide-gated channel; CNGB1; channel trafficking; rod photoreceptor; retinitis pigmentosa; apoptosis

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Received Sep 10, 2004; revised October 20, 2004; accepted November 12, 2004.

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