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

Abstract

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.

Phototransduction in mouse rods and cones

“…CNGB1 was found to be crucial for the targeting of the native CNG channel in rods. Thus, only trace amounts of the CNGA1 subunit were found on the ROS in CNGB1-null mice and the majority of rod photoreceptors failed to respond to light [106]. CNGA3-deficient mice selectively lost their cone photoresponse with the rod pathway intact.…”

“…Mouse models carrying null mutations of CNGB1 [106] and CNGA3 [107] are available. CNGB1 was found to be crucial for the targeting of the native CNG channel in rods.…”

Why photoreceptors die (and why they don't)

“…In a similar fashion, rods degenerate in animals (including humans) that lack functional cGMP-gated channels. (64,65) The knocking out of the channels should also cause a maintained lowering of the Ca 2þ concentration, since the entry pathway for Ca 2þ into the outer segment is eliminated, but there is one difficulty with this notion. The channel in the outer segment is tightly associated with the Na þ /Ca 2þ -K þ exchange protein, (66,67) with two exchanger molecules bound to each channel heteromer.…”

Loss of the Cholesterol-Binding Protein Prominin-1/CD133 Causes Disk Dysmorphogenesis and Photoreceptor Degeneration

“…Indeed, mistargeting of other OS proteins similarly leads to rod degeneration, as shown in a mouse model lacking the regulatory subunit Cngb1 of the rod cyclic nucleotide gated channel (Hüttl et al, 2005). We speculate that the disk dysmorphogenesis, in association with the defects in visual pigment sorting, not only impaired phototransduction, but also may have predisposed photoreceptors to degeneration in Prom-1 Ϫ/Ϫ mice (although, as discussed above, we cannot formally conclude that one is causally linked to the other).…”