Article

Adhesion G Protein-Coupled Receptors: Signaling, Pharmacology, and Mechanisms of Activation

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Molecular pharmacology (Impact Factor: 4.13). 07/2012; 82(5):777-83. DOI: 10.1124/mol.112.080309
Source: PubMed

ABSTRACT

The adhesion G protein-coupled receptors (GPCRs) are a distinct family of more than 30 receptors in vertebrate genomes. These receptors have been shown to play pivotal roles in a diverse range of biological functions and are characterized by extremely large N termini featuring various adhesion domains capable of mediating cell-cell and cell-matrix interactions. The adhesion GPCR N termini also contain GPCR proteolytic site motifs that undergo autocatalytic cleavage during receptor processing to create mature GPCRs existing as noncovalently attached complexes between the N terminus and transmembrane regions. There is mounting evidence that adhesion GPCRs can couple to G proteins to activate a variety of different downstream signaling pathways. Furthermore, recent studies have demonstrated that adhesion GPCR N termini can bind to multiple ligands, which may differentially activate receptor signaling and/or mediate cell adhesion. In addition, studies on several distinct adhesion GPCRs have revealed that truncations of the N termini result in constitutively active receptors, suggesting a model of receptor activation in which removal of the N terminus may be a key event in stimulating receptor signaling. Because mutations to certain adhesion GPCRs cause human disease and because many members of this receptor family exhibit highly discrete distribution patterns in different tissues, the adhesion GPCRs represent a class of potentially important drug targets that have not yet been exploited. For this reason, understanding the mechanisms of activation for these receptors and elucidating their downstream signaling pathways can provide insights with the potential to lead to novel therapeutic agents.

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Available from: Randy A. Hall, Aug 20, 2015
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    • "Deletion of the NTF (equivalent to PC1NTF) resulted in constitutive activation for some aGPCRs[50,51], suggesting that NTF association might normally prevent constitutive activation. This finding has led to the suggestion that such cleavage and association may allow regulation of aGPCR activity[15,49,50,52]. PC1 shares most of these structural elements, albeit it has only one disulfide bond, C3015-C3043, as depicted in Figure 2. "
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    ABSTRACT: Polycystin-1 (PC1) plays an essential role in renal tubular morphogenesis, and PC1 dysfunction causes human autosomal dominant polycystic kidney disease. A fundamental characteristic of PC1 is post-translational modification via cleavage at the juxtamembrane GPCR proteolysis site (GPS) motif that is part of the larger GAIN domain. Given the considerable biochemical complexity of PC1 molecules generated in vivo by this process, GPS cleavage has several profound implications on the intracellular trafficking and localization in association with their particular function. The critical nature of GPS cleavage is further emphasized by the increasing numbers of PKD1 mutations that significantly affect this cleavage process. The GAIN domain with the GPS motif therefore represents the key structural element with fundamental importance for PC1 and might be polycystic kidney disease's (PKD) Achilles' heel in a large spectrum of PKD1 missense mutations. We highlight the central roles of PC1 cleavage for the regulation of its biogenesis, intracellular trafficking and function, as well as its significance in polycystic kidney disease.
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    • "It remains open whether these mutations contribute to tumor formation or are just a reflection of the higher tumor mutation rates. Perhaps ECD mutations hamper cell-cell or cell-matrix interactions owing to decreased adhesive capacity (Lagerström and Schiöth, 2008; Paavola and Hall, 2012). It is reasonable to assume that mutations in the ECD region could also affect potential ligandbinding properties or prevent NTF modulation and Stachelmediated receptor activation. "

    Full-text · Dataset · Sep 2015
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    • "It remains open whether these mutations contribute to tumor formation or are just a reflection of the higher tumor mutation rates. Perhaps ECD mutations hamper cell-cell or cell-matrix interactions owing to decreased adhesive capacity (Lagerström and Schiöth, 2008; Paavola and Hall, 2012). It is reasonable to assume that mutations in the ECD region could also affect potential ligandbinding properties or prevent NTF modulation and Stachelmediated receptor activation. "

    Full-text · Dataset · Sep 2015
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