Scope Of Book

This book describes the principal mechanisms for signal transduction through activation of GPCRs and their interactions with G proteins. Fairly recently, it was discovered that GPCRs can also signal through alternative pathways without interactions with G proteins. This finding has cast doubts on the correctness of naming these receptors GPCRs. Rather it has been suggested that the scientific community refer to them as seven transmembrane (7TM) receptors based on their common structural topologies of seven transmembrane-spanning domains. These 7TM receptors can interact with many proteins other than G proteins to modulate signal transduction. Since most of the 7TM receptors mediate signal transduction through G proteins, it is therefore still relevant to call them GPCRs.

Chapter 2 describes the signal transduction mechanisms in detail and includes various examples. The importance of the GPCRs to drug discovery in general and as drug targets is outlined in Chapter 3. Specific areas of medicine such as cardio vascular disease (Chapter 4), cancer (Chapter 5), metabolic disease (Chapter 6), and neuroscience including neurodegeneration and psychiatry indicators (Chapter 7) are also covered. Chapter 9 is dedicated to high throughput screening methods for GPCRs that naturally play important roles in modern drug discovery.

Much attention has been paid to the structural biology of GPCRs. Such efforts can open new avenues for designing drugs with higher levels of potency and engineering specificity to certain GPCRs. Although bovine rhodopsin is the only GPCR for which a high resolution structure has been obtained to date, the strong trend today is to make serious investments in this area. Because structural biology demands milligram quantities of proteins, a need exists to develop robust expression systems for GPCRs.

Since most GPCRs are not overexpressed intrinsically in vivo and in situ, the facilitation of high-level recombinant heterologous expression systems has been one of the major bottlenecks in investigating the structural biologies of membrane proteins. Obviously, recombinant GPCR expression also serves an important function in the drug screening process. All applied and potentially interesting expression systems are described in Chapter 8. In silico methods including application of bioinformatics and molecular modeling for GPCRs as tools to support structural biology approaches are covered in Chapter 10. Chapter 11 provides further insight into structural biology identification and deals with the structures and dynamics of GPCRs using rhodopsin as a model protein. Chapter 12 deals with the problems and recent development in crystallization of GPCRs, and Chapter 13 demonstrates how novel solid-state NMR methods can be applied to GPCRs. Chapter 14 is an overview of several recently established national and international networks that bring together expertise from various areas — expression, purification, and crystallization — as a means to study a large number of GPCRs in parallel.

Finally, the dimerization phenomenon, originally considered a curiosity, has been demonstrated to occur much more frequently than originally anticipated through improved analytical methods. The importance of dimerization in relation to drug discovery is described in Chapter 15. Such interactions provide more avenues for G protein activation and potential drug design. Another issue of great interest, especially in relation to the development of novel drugs, is the discovery of a large number of orphan receptors and the extensive subsequent program of their deorpha-nization, presented in Chapter 16.

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