Rhodopsin is the primary photoreceptor molecule in the visual signal transduction and a prototype G-protein-coupled receptor (GPCR). The dogma that GPCRs—and especially rhodopsin—function as monomers has been unsettled by our direct visualization of rhodopsin dimers and higher oligomers in native disk membranes using electron and atomic force microscopy. In addition, new aspects on the onset and reasons for the hereditary diseases of the eye retina, Retinitis Pigmentosa, have emerged based on our findings.

G-protein-coupled receptors (GPCRs) represent the largest family of cell-surface receptors and are encoded by >1,000 genes in the human genome. GPCRs mediate the biological effects of light, hormones, neurotransmitters, chemokines, and sensory stimuli, and are involved in many central functions of the human body in health and disease. Therefore, GPCRs are targets of a large number of therapeutics and provide opportunities for the development of new drugs with applications in all clinical fields. Examples of GPCRs that can be biochemically detected in homo- or heteromeric complexes are reported at an accelerated rate. They not only indicate that many GPCRs exist as homodimers and heterodimers, but also that their oligomeric assembly could have important functional roles. Our discovery of the higher organization of the archetypal GPCR rhodopsin in disk membranes is an essential step towards understanding these functions. The emerging recognition of GPCR dimers and higher oligomers is likely to have important implications for the development and screening of new drugs. In addition to this general aspect on the structure-function relationship of GPCRs, a pharmacologically interesting aspect has emerged from our findings: certain mutations in rhodopsin cause breakdown in the function of the retina. This group of hereditary diseases of the eye retina is named Retinitis Pigmentosa. Based on our observations from electron and atomic force microscopy, disruption of the dimeric and oligomeric configuration of rhodopsin would hinder the binding of the cognate proteins, e.g., rhodopsin kinase, transducin, and arrestin, upon activation by light resulting in a breakdown in the function. In the future, we will be able to study the organization of rhodopsin in disk membranes from transgenic mice harboring specific Retinitis Pigmentosa mutations and screen for drugs that restore the native organization of rhodopsin.

In pursuit of understanding membrane protein structure and function we have established high-resolution electron and atomic force microscopy (AFM) in our laboratory. In particular, the desire to visualize single-membrane proteins in their native membrane has motivated us to push the AFM technique during the last decade. Nowadays, we can routinely visualize the surface of single-membrane proteins under native conditions to a lateral resolution of 0.4 nm and a vertical resolution of 0.1 nm. For the elucidation of the organization of rhodopsin and opsin in the native membrane, our laboratory has teamed up with Kris Palczewski, whose laboratory at the University of Washington Department of Ophthalmology is recognized as one of the leaders in vision research and has solved the atomic structure of rhodopsin.

Light is collected by rod and cone receptor cells in the eye's retina to produce visual signals. Rods contain the receptor molecule rhodopsin, which triggers a chain reaction leading to a nerve impulse upon detection of light. A group of eye diseases named Retinitis Pigmentosa cause breakdown in the function of the rods and cones. Until recently, it was believed that rhodopsin functions as a single molecule. Our work demonstrated for the first time that rhodopsin exists in rows of pairs in its native environment. Based on our result, we showed that disruption of rhodopsin's organization in the eye by specific mutations in the gene coding for rhodopsin may cause certain forms of the Retinitis Pigmentosa disease. Visualization of rhodopsin was performed by electron microscopy and particularly by a new sophisticated microscopy technique called atomic force microscopy. This discovery on the organization of rhodopsin led to a reconsideration of how the first steps in vision work. In addition, potential factors leading to the onset of Retinitis Pigmentosa diseases were established based on our structural data. Importantly, rhodopsin is just one example of a receptor type of which more than a thousand exist in the human body. It now seems likely that most of these receptors also function as paired molecules, which has many implications for our health.