Their findings are reported in today's issue of Neuron.

In the disease retinitis pigmentosa (RP), the photoreceptor cells in the eye degenerate and gradually die. As a result, an initial difficulty in seeing in poor light is superseded by peripheral (and sometimes complete) blindness.

While researchers have known for some time that a protein called CNGA1 is mutated in some cases of retinitis pigmentosa, it was not clear how the mutated protein caused the disease.

CNGA1 and the related protein, CNGB1, are located at the outer edges of the retinal photoreceptors and together form ion channels that convert activation by light into an electrical signal that is ultimately carried to the brain.

CNGA1 can co-assemble with itself or with CNGB1 to form functional channels. These channels are composed of four subunits and are put together from component parts inside the cell before being shuttled to the surface of the photoreceptor cell.

Both the assembly of the channel complex and the shuttling of the channel complex to the surface of the photoreceptor are critical to forming a fully functional channel.

In exploring the mechanisms that underlie the defects associated with CNGA1 mutations, Matthew Trudeau and William Zagotta at the University of Washington observed that when CNGA1 was mutated at a particular amino acid residue (as it is in some cases of RP), they could no longer find channel complexes containing both CNGA1 and CNGB1 on the surface of the cells.

They then went on to show that the lack of surface expression of CNGA1/CNGB1 complexes was due to the fact that the mutated CNGA1 was no longer able to bind to CNGB1.

Importantly, they were also able to show that the binding between normal CNGA1 and CNGB1 acts to mask or hide a signal on CNGB1 that prevents trafficking of CNGB1 to the surface. So, when CNGA1 is mutated, it cannot bind to CNGB1; this in turn leaves the signal on CNGB1 exposed and CNGB1 is unable to shuttle to the cell surface.

The ultimate result is that the functional channel complexes necessary for converting a light signal into an electrical one do not make it to the surface of the photoreceptor cells in the retina.

Trudeau and Zagotta suggest that in some cases of RP, photoreceptor cells may degenerate as a secondary consequence of failing to express these channels on the surface and that addressing this deficiency (perhaps by artificially masking the signal that prevents shuttling of CNGB1 to the surface) might be one way of combating this disease.

[Contact: William N. Zagotta]

11-Apr-2002