“The emerging recognition of GPCR dimers and higher oligomers is likely to have important implications for the development and screening of new drugs.”

Rhodopsin is the primary photoreceptor molecule in the visual signal transduction and a prototype G-protein-coupled receptor (GPCR). The dogma that rhodopsin functions as a monomer has been unsettled by our direct visualization of rhodopsin dimers and higher oligomers in native disk membranes using atomic-force microscopy.

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 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 drug candidates with potential 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 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 pursuit of understanding membrane protein structure and function we have established atomic-force microscopy at the sub-nanometer level. With this technique it is possible to visualize membrane protein surfaces under native conditions to a lateral resolution of 0.4 nm and a vertical resolution of 0.1 nm. We were interested in unraveling the packing of rhodopsin in the most native state, i.e., in the disk membrane. Therefore, our laboratory has teamed up with Kris Palczewski, whose laboratory has solved the 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. Until recently it was believed that rhodopsin functions as a single molecule. Our work demonstrates for the first time that rhodopsin exists in rows of pairs in its native environment. Our images were taken using a sophisticated microscopy technique called atomic-force microscopy. This discovery led to a reconsideration of how the first steps in vision work. 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.