Rhodopsin and the others: a historical perspective on structural studies of G protein-coupled receptors.

The role of rhodopsin as a structural prototype for the study of the whole superfamily of G protein-coupled receptors (GPCRs) is reviewed in an historical perspective. Discovered at the end of the nineteenth century, fully sequenced since the early 1980s, and with direct three-dimensional information available since the 1990s, rhodopsin has served as a platform to gather indirect information on the structure of the other superfamily members. Recent breakthroughs have elicited the solution of the structures of additional receptors, namely the beta(1)- and beta(2)-adrenergic receptors and the A(2A) adenosine receptor, now providing an opportunity to gauge the accuracy of homology modeling and molecular docking techniques and to perfect the computational protocol. Notably, in coordination with the solution of the structure of the A(2A) adenosine receptor, the first "critical assessment of GPCR structural modeling and docking" has been organized, the results of which highlighted that the construction of accurate models, although challenging, is certainly achievable. The docking of the ligands and the scoring of the poses clearly emerged as the most difficult components. A further goal in the field is certainly to derive the structure of receptors in their signaling state, possibly in complex with agonists. These advances, coupled with the introduction of more sophisticated modeling algorithms and the increase in computer power, raise the expectation for a substantial boost of the robustness and accuracy of computer-aided drug discovery techniques in the coming years.

Rhodopsin phosphorylation: 30 years later.

Phototransduction in vertebrate photoreceptor cells mediated by rhodopsin is one of the most comprehensively examined G protein-coupled receptor (GPCR) signaling pathways. The signal transduction pathway can be mapped from the initial absorption of light to conformational changes within rhodopsin, through activation of the G protein transducin, and to the ultimate closure of the cation cGMP-gated channels in the plasma membrane. Furthermore, phototransduction has become an intensely studied model system for understanding the desensitizing processes that allow reduced non-linear responses of photoreceptor cells to increasing levels of illumination. Although some general themes appear to occur in GPCR systems, the details of these desensitizing processes are likely to be specific to each of the receptors. These differences are attributed to the fact that each receptor has unique kinetic constraints, amplification levels, tolerance to basal constitutive activity, intracellular internalization and recycling, redundancy of isoforms, and morphologies of the cell of their expression. One of the biochemical processes that are believed to be a common part of this desensitization of the GPCR-mediated cascade is receptor phosphorylation catalyzed by members of a small family of the GPCR kinases. The enzymatic, physiological and genetic aspects of rhodopsin phosphorylation and rhodopsin kinase have been characterized extensively over the last 30 yr. However, new structurally based approaches to examining rhodopsin kinase and rhodopsin phosphorylation are still awaiting further investigations. We present here a summary of the current understanding of rhodopsin phosphorylation and the properties of rhodopsin kinase, along with some expectations of future investigations into these topics.

The superfamily of heptahelical receptors.

Despite a growing appreciation of functional analogies between visual and hormonal signalling systems in the early 1980s, the discovery of the close structural relationship between rhodopsin and the beta2-adrenergic receptor, and of the existence of a larger 'superfamily' of such receptors, came as a total surprise. Here I provide a personal perspective on events leading up to and flowing from this exciting discovery that opened up a vast field of research.

George Wald memorial talk.

George Wald was born in 1906 in New York City to immigrant parents. An early and voracious reader, he soon developed a wide range of interests and entered New York University as a pre-law student, the first in his family to attend college. Shortly shifting to pre-medicine, he graduated college in biology. For graduate work, he joined the laboratory of Selig Hecht, a pioneer in vision research, at Columbia University. In 1932, four months before Hitler came to power, George went to Berlin to do postdoctoral work in the laboratory of Otto Warburg and there found vitamin A in the retina. This launched his life-long explorations of the molecular basis of vision for which he received the Nobel Prize in Physiology or Medicine in 1967. During the 1960s, George became increasingly involved in anti-war and anti-nuclear activities, writing and travelling widely, including multiple trips to commemorations of the bombings of Hiroshima and Nagasaki sponsored by Japanese colleagues. He considered these activities part of being a biologist, someone concerned with life. In his final years, he turned to questions about consciousness, writing and speaking about 'Life and Mind in the Universe'.

100 years of the visual cycle.

One--hundred years have passed since Franz Boll and Willy Kühne first characterized rhodopsin and discovered the visual pigment cycle. Some of the events and individuals of that period are described, and color photographs are presented to show the appearance of rhodopsin in the living retina.