The very first monograph that was dedicated to a general overview on the adhesion family of G protein-coupled receptors (aGPCRs) was published just in 2010 (Adhesion-GPCRs: Structure to Function. Yona and Stacey, Ed., Landes Biosci-ence and Springer). It was the earliest attempt by a small group of researchers to cast the scarce information on these enigmatic molecules into a general concept on what they do and how they do it.
The absence of such public face for the biology of aGPCRs was painfully felt by all colleagues who were actively researching aGPCRs in these days. Scepticism was high from many neighbouring fields why aGPCRs rise to such grotesque dimensions with thousands of residues dedicated to their extracellular tails alone. Also how their exotic functions during the development of organs could be accounted for by their peculiar bipartite adhesive/receptive structure was a constant source of doubt (and motivation for further investigation). Not least, whether aGPCRs are 'true' GPCRs and can thus be attacked by the immense technological armoury that has accumulated during the decades of research on other members of the GPCR superfamily was possibly the most pressing question we were confronted with. Next to the simple matter: what do these receptors sense, after all?
While many of these points could not be satisfactorily answered yet back then, the 2010 book project brought them on the map for the first time in a collective effort. Therefore, this venture from a group of adhesion GPCR aficionados was an incontestable sign of a growing community of researchers that had formed to pursue the inherent questions on aGPCRs with seriousness and persistence.
The roster of colleagues that have contributed their expertise, time and dedication to the current monograph bears testimony to that spirit, and we are immensely grateful for their support. We also wish to thank the Editorial Board of the Handbook of Experimental Pharmacology for allotting us an entire volume of this eminent book series to document our knowledge on aGPCRs. We are indebted to Susanne Dathe, Wilma McHugh, Rahila Nahid and Sumathy Thanigaivelu from Springer Nature for excellent editorial and technical support, and for generous funding from the Deutsche Forschungsgemeinschaft (DFG) to several chapter authors through a Research Unit Grant (FOR 2149), a first award of its kind to a coordinated scientific initiative dedicated to the study of aGPCRs.
The chapters of this volume are authored by renowned experts in the aGPCR field and chart the current state of aGPCR research. Following their contributions, the reader will learn that some of the pressing molecular issues of 2010 have begun to find answers:• aGPCRs can signal via canonical signaling outlets and a credible mechanism on how they get activated has been recently devised (Liebscher et al., Tethered agonism: a common activation mechanism of adhesion GPCRs; Kishore et al., Versatile signaling activity of adhesion GPCRs). • In some cases, the receptors' structural peculiarities have been experimentally, matched with highly intriguing biochemical and biological phenomena such as in the case of the GAIN domain and other extracellular protein folds (Arac et al., Understanding the structural basis of adhesion GPCR functions). • One such class of events regards the extensive proteoly tic processing of aGPCRs and is discussed by Nieberler et al. (Control of adhesion GPCR function through proteolytic processing). Knapp et al. explore the central position of adhesion GPCRs-related protein networks, roles that are mainly relayed through their intracellular domains. • Other vital components of their architecture such as the structure of the heptahelical transmembrane domain of aGPCRs have remained locked to our efforts, but it is clear that in the near future the focus will shift evermore into their direction and offer new vantage points to interfere with their activity. Nijmeijer et al. explored these possibilities in their chapter on 7TM domain structure of adhesion GPCRs. • Kovacs et al. review the relevance of genomic signatures at adhesion GPCR loci (specifically of human homologs), informing us about their role in phenotypic variation and disease aetiology, an overdue endeavour in the omics era that is aided by the novel harmonised nomenclature and classification system of the aGPCR family introduced by Krishnan et al. (Classification, nomenclature and structural aspects of adhesion GPCRs).
The second part of this book is dedicated to physiological and pathological aspects of aGPCRs: •Scholz et al. describe the emerging concept of adhesion GPCRs as a putative class of metabotropic mechanosensors, which distinguishes them from the rest of the GPCR superfamiry. • Several chapters relate to this discovery with specialist focus on its implications in the nervous system (Harty et al., Adhesion GPCRs as novel actors in neural and glial cell functions: from synaptogenesis to myelination), in skeletal muscle (White et al., Control of skeletal muscle cell growth and size through adhesion GPCRs) and lung physiology (Ludwig et al., Adhesion GPCR function in pulmonary development and disease) and in the immune system (Hamann et al., Adhesion GPCRs as modulators of immune cell function). Musa et al. describe that heart development, angiogenesis and blood-brain barrier function are modulated by adhesion GPCRs, adding further organ systems that require those receptors for their respective setups and daily operatioos. • Finally, Strutt et al. discuss that adhesion GPCRs govern polarity of epithelia and cell migration, while the chapter of Aust et al. review the current state of knowledge on adhesion GPCRs in tumorigenesis.
We are certain that the research described in this book marks several milestones in the maturation of our understanding on how aGPCRs impact biology. It is to be hoped that the concepts on several aspects of aGPCRs unveiled in the last years are stepping stones to grasp their roles in human disease and therapeutic intervention. We are much looking forward to witness and participate in the exciting developments of this thriving area of biomedical research.
The book will start though with look back at the History of the adhesion GPCR field (Hamann and Petrenko), to record the path of our community and remark its scientific course throughout the last 20 years. Wiirzburg, Germany Tobias Langenhan; Leipzig, Germany Torsten Schoneberg

Introduction: History of the Adhesion GPCR Field 1

Part I Molecular and Pharmacological Properties of Adhesion GPCRs

Classification, Nomenclature, and Structural Aspects of Adhesion GPCRs 15

7TM Domain Structure of Adhesion GPCRs 43

Understanding the Structural Basis of Adhesion GPCR Functions 67

Control of Adhesion GPCR Function Through Proteolytic Processing 83

Tethered Agonism: A Common Activation Mechanism of Adhesion GPCRs 111

Versatile Signaling Activity of Adhesion GPCRs 127

Adhesion GPCR-Related Protein Networks 147

The Relevance of Genomic Signatures at Adhesion GPCR Loci in Humans 179

Part II Adhesion GPCRs as Pharmakotargets in Organ Function and Development

Adhesion GPCRs as a Putative Class of Metabotropic Mechanosensors 221

Adhesion GPCRs Govern Polarity of Epithelia and Cell Migration 249

Adhesion GPCRs as Novel Actors in Neural and Glial Cell Functions: From Synaptogenesis to Myelination 275

Control of Skeletal Muscle Cell Growth and Size Through Adhesion GPCRs 299

Adhesion GPCR Function in Pulmonary Development and Disease 309

Adhesion GPCRs as Modulators of Immune Cell Function 329

Heart Development, Angiogenesis, and Blood-Brain Barrier Function Is Modulated by Adhesion GPCRs 351

Adhesion GPCRs in Tumorigenesis 369

Index 397

中国医科院医学信息研究所