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Functional interchangeability of rod and cone transducin alpha-subunits.

ABSTRACT: Rod and cone photoreceptors use similar but distinct sets of phototransduction proteins to achieve different functional properties, suitable for their role as dim and bright light receptors, respectively. For example, rod and cone visual pigments couple to distinct variants of the heterotrimeric G protein transducin. However, the role of the structural differences between rod and cone transducin alpha subunits (Talpha) in determining the functional differences between rods and cones is unknown. To address this question, we studied the translocation and signaling properties of rod Talpha expressed in cones and cone Talpha expressed in rods in three mouse strains: rod Talpha knockout, cone Talpha GNAT2(cpfl3) mutant, and rod and cone Talpha double mutant rd17 mouse. Surprisingly, although the rod/cone Talpha are only 79% identical, exogenously expressed rod or cone Talpha localized and translocated identically to endogenous Talpha in each photoreceptor type. Moreover, exogenously expressed rod or cone Talpha rescued electroretinogram responses (ERGs) in mice lacking functional cone or rod Talpha, respectively. Ex vivo transretinal ERG and single-cell recordings from rd17 retinas treated with rod or cone Talpha showed comparable rod sensitivity and response kinetics. These results demonstrate that cone Talpha forms a functional heterotrimeric G protein complex in rods and that rod and cone Talpha couple equally well to the rod phototransduction cascade. Thus, rod and cone transducin alpha-subunits are functionally interchangeable and their signaling properties do not contribute to the intrinsic light sensitivity differences between rods and cones. Additionally, the technology used here could be adapted for any such homologue swap desired.

SUBMITTER: Deng WT

PROVIDER: S-EPMC2758286 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cone rod dystrophies (CRDs) (prevalence 1/40,000) are inherited retinal dystrophies that belong to the group of pigmentary retinopathies. CRDs are characterized by retinal pigment deposits visible on fundus examination, predominantly localized to the macular region. In contrast to typical retinitis pigmentosa (RP), also called the rod cone dystrophies (RCDs) resulting from the primary loss in rod photoreceptors and later followed by the secondary loss in cone photoreceptors, CRDs reflect the opposite sequence of events. CRD is characterized by primary cone involvement, or, sometimes, by concomitant loss of both cones and rods that explains the predominant symptoms of CRDs: decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness. The clinical course of CRDs is generally more severe and rapid than that of RCDs, leading to earlier legal blindness and disability. At end stage, however, CRDs do not differ from RCDs. CRDs are most frequently non syndromic, but they may also be part of several syndromes, such as Bardet Biedl syndrome and Spinocerebellar Ataxia Type 7 (SCA7). Non syndromic CRDs are genetically heterogeneous (ten cloned genes and three loci have been identified so far). The four major causative genes involved in the pathogenesis of CRDs are ABCA4 (which causes Stargardt disease and also 30 to 60% of autosomal recessive CRDs), CRX and GUCY2D (which are responsible for many reported cases of autosomal dominant CRDs), and RPGR (which causes about 2/3 of X-linked RP and also an undetermined percentage of X-linked CRDs). It is likely that highly deleterious mutations in genes that otherwise cause RP or macular dystrophy may also lead to CRDs. The diagnosis of CRDs is based on clinical history, fundus examination and electroretinogram. Molecular diagnosis can be made for some genes, genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, and the visual prognosis is poor. Management aims at slowing down the degenerative process, treating the complications and helping patients to cope with the social and psychological impact of blindness.

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Functional interchangeability of rod and cone transducin alpha-subunits.

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