A key role for cyclic nucleotide gated (CNG) channels in cGMP-related retinitis pigmentosa

Abstract

The rd1 natural mutant is one of the first and probably the most commonly studied mouse model for retinitis pigmentosa (RP), a severe and frequently blinding human retinal degeneration. In several decades of research, the link between the increase in photoreceptor cGMP levels and the extremely rapid cell death gave rise to a number of hypotheses. Here, we provide clear evidence that the presence of cyclic nucleotide gated (CNG) channels in the outer segment membrane is the key to rod photoreceptor loss. In Cngb1(-/-) × rd1 double mutants devoid of regular CNG channels, cGMP levels are still pathologically high, but rod photoreceptor viability and outer segment morphology are greatly improved. Importantly, cone photoreceptors, the basis for high-resolution daylight and colour vision, survived and remained functional for extended periods of time. These findings strongly support the hypothesis of deleterious calcium (Ca(2+))-influx as the cause of rapid rod cell death and highlight the importance of CNG channels in this process. Furthermore, our findings suggest that targeting rod CNG channels, rather than general Ca(2+)-channel blockade, is a most promising symptomatic approach to treat otherwise incurable forms of cGMP-related RP.

Lysosomal membrane permeabilization and autophagy blockade contribute to photoreceptor cell death in a mouse model of retinitis pigmentosa

“…28 In the rd1 model of retinitis pigmentosa, abnormal calcium accumulation in photoreceptor cells has been linked to cell death independently of cGMP levels. 29 Several studies have also implicated intracellular calcium in autophagy regulation, 30 and the differing outcomes described suggest that calciumdependent autophagy regulation may be both cell-and context-dependent. 31 Some reports indicate autophagy Lysosomal damage in retinitis pigmentosa N Rodríguez-Muela et al activation after calcium overload, while others have described autophagy blockade before autophagosome closure in response to thapsigargin or the calcium ionophore A23187.…”

Retinal degeneration depends on Bmi1 function and reactivation of cell cycle proteins

“…Several studies have attempted to rescue or delay retinal degeneration in Rd1 mice with neurotrophic factors (2), calcium blockers (3), or antiapoptotic gene transfer (4), but these neuroprotective approaches never exceeded modest or temporary effects. Interestingly, deleting cyclic nucleotide channel-b1 (CNGB1), which is constantly stimulated by the accumulation of cyclic GMP (cGMP) in Rd1 photoreceptors, leads to a marked rescue of the sensory cells (5). Because an elevated level of cGMP is believed to be an early event in the induction of cell death in this model, these results can be considered as a milestone reference to conduct the identification of other candidates involved in the photoreceptor death process.…”

Inhibition of Mitochondrial Pyruvate Transport by Zaprinast Causes Massive Accumulation of Aspartate at the Expense of Glutamate in the Retina

“…Pde6bϩ mice were used as the background control for rd1 mice. Cyclic nucleotide gated channel ␤1 knock-out (Cngb1 Ϫ/Ϫ ) mice on C57BL/6 background were obtained from the Institute for Ophthalmic Research, Tuebingen, Germany (19,20). Aralar/AGC1 ϩ/Ϫ mice (21) were crossed to produce Aralar/AGC1 Ϫ/Ϫ and Aralar/AGC1 ϩ/ϩ control littermates in Sv129/C57BL6 background at Dr. Jorgina Satrústegui's laboratory (Madrid, Spain).…”

“…To test whether cyclic nucleotide-gated channels and Ca 2ϩ are involved in the decrease of glutamate, we used the retina from Cngb1 Ϫ/Ϫ mice in which the rising cGMP could not activate cyclic nucleotide gated channels to cause depolarization and elevation of intracellular free Ca 2ϩ (19,29). Remarkably, Zaprinast decreased glutamate and increased aspartate in Cngb1 Ϫ/Ϫ retina (Fig.…”