Rhodopsin Structure, Function, and Involvement in Retinitis Pigmentosa

HISTORICAL PERSPECTIVE

Systematic investigation into photoreception can be traced back to the years following the scientific revolution (Fig. 1A) when geographer, microscope enthusiast, and pioneer of microbiology Anton van Leeuwenhoek first observed retinal rod and cone cells in 1722, providing the first suggestion that light reception may occur somewhere other than at the lens. Thomas Young, famed for the double-slit experiment leading to the wave theory of light, subsequently proposed that color perception depends on three different color-sensitive nerve fibers, later defined by Hermann von Helmholtz to be blue, green, and red, a theory so advanced it was not proven until a century later. Heinrich Mueller suggested that retina rod and cone cells were involved in photoreception, further stimulating investigations into the retina. Franciscus Donders, around 1857, coined the term retinitis pigmentosa in a letter to Helmholz describing spicules of pigmentation he found throughout a patient’s degenerated retina.

The discovery of rhodopsin is owed to the combined efforts of Franz Boll and Willy Kühne through an interesting series of exchanges reviewed elsewhere [2]. Bloch linked night blindness to malnutrition in 1917, from which Blegvad subsequently identified the deficient agent to be vitamin A. Involvement of vitamin A deficiency in night blindness provided supplemental evidence in the seminal identification of the active combination of vitamin A and opsin in 1935 by Wald (Fig. 1B), whose accomplishments have enabled incalculable benefits in vision research [3]. Over the past three decades, astounding progress has been made since the discovery of the opsin gene by Nathans [4]; these include the discovery of naturally occurring mutations leading to retinitis pigmentosa [5], deciphering the signaling pathway through transducin [6–12], determination of critical structural features such as the Schiff’s base counterion [13] and disulfide bond [14, 15], electron cryomicroscopy structure [16, 17], conformational movements required for activation [18, 19], and the crystal structure of rhodopsin [20] (Fig. 1C). Further details of activation are being intensely investigated at the molecular and biophysical levels [8, 21, 22]. Insights into the nature of misfolded rhodopsin [23–29] and dimeric packing of rhodopsin [30–34] have also been major achievements. This exponential rate of discovery will likely unfold many further details on the intriguing structure and function of the opsin protein and disease associations.

RHODOPSIN AS THE PROTOTYPICAL

G PROTEIN-COUPLED RECEPTOR

Rhodopsin receives considerable research interest, particularly in structural and functional studies, owing in part to its reputation as the prototypical member of the seven-transmembrane-spanning, guanine nucleotide-binding protein (G protein)-coupled receptor superfamily, which accounts for approximately 5% of genes in the human genome. The G protein-coupled receptors (GPCRs) are arguably among the most medically important protein families as over 30% of available pharmaceuticals target proteins within this family [35]. Furthermore, rhodopsin remains the only crystallographic structure available to represent the GPCR superfamily. GPCRs are generally responsible for transmitting extracellular information into the cellular environment with ligand stimuli covering the range of biochemical diversity: large macromolecules, peptides, amino acids, nucleic acids, lipids, ions, and even, as with rhodopsin, a single photon of light.