Alterations in the photoactivation pathway of rhodopsin mutants associated with retinitis pigmentosa.

The visual photoreceptor rhodopsin undergoes a series of conformational changes upon light activation, eventually leading to the active metarhodopsin II conformation, which is able to bind and activate the G-protein, transducin. We have previously shown that mutant rhodopsins G51V and G89D, associated with retinitis pigmentosa, present photobleaching patterns characterized by the formation of altered photointermediates whose nature remained obscure. Our current detailed UV-visible spectroscopic analysis, together with functional characterization, indicate that these mutations influence the relative stability of the different metarhodopsin photointermediates by altering their equilibria and maintaining the receptor in a nonfunctional light-induced conformation that may be toxic to photoreceptor cells. We propose that G51V and G89D shift the equilibrium from metarhodopsin I towards an intermediate, recently named as metarhodopsin Ib, proposed to interact with transducin without activating it. This may be one of the causes contributing to the molecular mechanisms underlying cell death associated with some retinitis pigmentosa mutations. Mutations in the transmembrane domain of rhodopsin, associated with retinitis pigmentosa, present altered photobleaching patterns. These are characterized by the formation of non-functional metarhodopsin I-like photointermediates that would abnormally accumulate, causing toxic effects on photoreceptor cells and leading to their degeneration. This finding adds on the complexity of molecular mechanisms, other than protein misfolding, associated with retinitis pigmentosa retinal degeneration. [ABSTRACT FROM AUTHOR]