A guide to adhesion GPCR research

Abstract

Adhesion G protein‐coupled receptors (aGPCRs) 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 aGPCRs form 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 aGPCR 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 aGPCRs 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 aGPCR research and identify strategies to tackle them. Furthermore, we discuss approaches how to promote, stimulate, and translate research on aGPCRs ‘from bench to bedside’ in the future.

An apical membrane complex for triggering rhoptry exocytosis and invasion in Toxoplasma

“…Few GPCRs are annotated in the Toxoplasma and P. falciparum genomes (http://toxodb.org/; Fredriksson & Schiöth, 2005; Madeira et al , 2008), suggesting that they are highly divergent and therefore difficult to recognize in Apicomplexa. Because of CRMPs' potential host‐cell‐binding domains, they might be analogous to adhesion GPCRs, a sub‐group of proteins with a large extracellular part containing structural modules typical of cell adhesion proteins (Yona et al , 2008; Liebscher et al , 2021). Adhesion GPCRs convert the stimulus derived from cell–cell contact into intracellular signaling via their C‐termini, but many lacks identified activating ligands.…”

Ligands and Beyond: Mechanosensitive Adhesion GPCRs

“…The functional significance of aGPCRs has been amply documented in various physiological and pathological processes such as brain cortex development [17], immune regulation [18][19][20], fertility [21], and tumorigenesis [22,23]. While it is beyond the scope of the present review to discuss the functional roles of aGPCRs (please see [24,25] for detail), the underlying mechanisms for the diverse functions of aGPCRs are mainly due to their complex structural organization and diverse receptor activities that integrate extracellular adhesion and intracellular signaling [26]. Consequently, one of the major efforts in the aGPCR research field is the identification of their cognate endogenous and exogenous ligand molecules that trigger aGPCR activation.…”

An apical membrane complex controls rhoptry exocytosis and invasion in Toxoplasma

“…Few GPCRs are annotated in the Toxoplasma and P. falciparum genomes (Fredriksson and Schiöth, 2005; Madeira et al, 2008), suggesting that they are highly divergent and therefore difficult to recognize in Apicomplexa. Because of CRMPs’ potential host-cell-binding domains, they might be analogous to adhesion-GPCRs, a sub-group of proteins with a large extracellular part containing structural modules typical of cell adhesion proteins (Liebscher et al, 2021; Yona et al, 2008). Adhesion-GPCRs convert the stimulus derived from cell-to-cell contact into intracellular signaling via their C-termini, but many lack identified activating ligands.…”