A guide to adhesion GPCR research

A GUIDE TO. . . A guide to adhesion GPCR research

Adhesion G protein-coupled receptors are a class of structurally and functionally highly intriguing cell surface receptors with essential functions in health and disease. Thus, they display a vastly unexploited pharmacological potential. Our current understanding of the physiological functions and signaling mechanisms of adhesion G protein-coupled receptors forms the basis for elucidating further molecular aspects. Combining these with novel tools and methodologies from different fields tailored for studying these unusual receptors yields a powerful potential for pushing adhesion G protein-coupled receptor research from singular approaches toward building up an in-depth knowledge that will facilitate its translation to applied science. In this review, we summarize the state-of-the-art knowledge on adhesion G protein-coupled receptors in respect to structure-function relations, physiology, and clinical aspects, as well as the latest advances in the field. We highlight the upcoming most pressing topics in adhesion G protein-coupled receptor research and identify strategies to tackle them. Furthermore, we discuss approaches how to promote, stimulate, and translate research on adhesion G protein-coupled receptors from bench to bedside in the future.

Introduction

G protein-coupled receptors represent the largest family of membrane-bound receptors, mediating cellular responses to an immense number of diverse signals such as neurotransmitters, photons, and hormones. G protein-coupled receptors are involved in nearly all biological processes and represent the number one therapeutic target for many pathologies, including cardiovascular diseases, hypertension, diabetes, and substance abuse. Indeed, close to forty percent of all prescribed drugs target G protein-coupled receptors, positioning these receptors in the focus of academic scientists, clinicians, and pharmaceutical companies.

Adhesion G protein-coupled receptors are the second largest G protein-coupled receptor class (although comprising much fewer members than the largest class, the Rhodopsin-like G protein-coupled receptors), with unique structural as well as intriguing functional features. Adhesion G protein-coupled receptors are highly conserved and evolutionarily ancient receptors, present in most animals and even in some unicellular eukaryotes. In humans, thirty-three representative adhesion G protein-coupled receptors have been identified, with numerous splice variants contributing to an even larger structural variety with potential implications for signal transduction in most human tissues. Yet, surprisingly little is known about the characteristics and functionality of adhesion G protein-coupled receptors in human physiology and disease, making them one of the least understood G protein-coupled receptor class.

To date, three of thirty-three adhesion G protein-coupled receptors have been shown to cause human diseases. Mutants of the Very Large G protein-coupled Receptor VLGR1/ADGRV1 were identified in patients suffering from Usher syndrome type two. Several mutations in GPR56/ADGRG1 were found in patients with a severe brain malformation called bilateral frontoparietal polymicrogyria. Recently, a variant of the EGF-like module-containing mucin-like hormone receptor-like two, EMR2/ADGRE2 was identified in patients with autosomal dominant vibratory urticaria. Even though only these three adhesion G protein-coupled receptors have been causatively linked to monogenic human diseases so far, it is assumed that this receptor class contributes to polygenic diseases and to undiagnosed causes of embryonic lethality. This assumption is supported by multiple genome-wide association studies, linking various adhesion G protein-coupled receptors to metabolic or psychiatric diseases, and by knock-out of selected adhesion G protein-coupled receptors in animal models that cause embryonic death or perinatal lethality. Some adhesion G protein-coupled receptor knock-out animals that manage to survive to adulthood present with severe organ impairment such as accumulation of alveolar surfactant phospholipids, or myocardial hypertrophy. Neuronal cells were shown to require adhesion G protein-coupled receptor function to migrate and assume correct orientation, to recognize mechanosensory stimuli, control spatial learning and memory, as well as maintain myelination and axon repair. Reduction in male fertility has also been observed due to adhesion G protein-coupled receptor downregulation, while several studies have implicated these receptors in immune defense, metabolism and cancer.

In contrast to the obvious essential functions and the untapped pharmacological potential of adhesion G protein-coupled receptors, our understanding of their various physiological and pathophysiological roles contains huge gaps. These gaps are underscored by the complex architecture of these receptors - most of them extremely large proteins, which can reach up to six thousand five hundred amino acids. Their structural features suggest novel modes of signaling and there are indications that in addition to classic G protein-coupled signaling, they also engage actively in cellular adhesion and can be activated by mechanical stimuli.

Thus, research of the past two decades has revealed that adhesion G protein-coupled receptors are a class of G protein-coupled receptors with a diverse spectrum of physiological functions in health and disease, presenting not only tremendous pharmacological potential but also complex modes of action. This complexity extends on many levels - from numerous isoforms per receptor, which can have various functions, to multiple signaling pathways mediated through the modular architecture of adhesion G protein-coupled receptors - marking them not only a highly interesting class of G protein-coupled receptors but also a very challenging one to study. Research on many aspects of these receptors, such as elucidating the details of their molecular functions, their network of interactions, or a structural basis for their pharmacological manipulation is still lagging far behind other G protein-coupled receptor classes.

This review provides an overview on the current knowledge on adhesion G protein-coupled receptor structure-function relations, physiological roles, and clinical implications, thereby identifying knowledge gaps and the most pressing challenges in the field. We contemplate how these gaps can most efficiently be filled and the challenges tackled - through connecting academia, industry partners, and other stakeholders on an international level to successfully promote and foster future research on adhesion G protein-coupled receptors. One approach to achieve this is the currently running COST Action CA one eight two forty Adher'n Rise (Adhesion G Protein-Coupled Receptor Network: Research and Implementation Set the path for future Exploration).