In addition to their protein domain complexity, aGPCRs have been difficult to study due to their large size and complex genomic structures, with many small exons separated by very large introns. Recent data for multiple aGPCRs suggests that these proteins can function as adhesion molecules by virtue of the NTF, and as classical GPCRs that signal through G-proteins by virtue of the CTF, in addition to the roles the NTF and CTF have in concert with one another. In other proteins, these “adhesion” domains ( e.g., EGF-like domains and cadherin domains) are involved in protein-protein, cell-matrix, and cell-cell interactions, leading to the idea that they perform similar functions in aGPCRs. The “adhesion” classification was given to this family of GPCRs due to the large number of classical cell adhesion domains found in the NTFs of many of these receptors. Most aGPCRs undergo autoproteolysis at the GPS motif, which results in a protein that is separated into an N-terminal fragment (NTF) and C-terminal fragment (CTF) that are thought to remain non-covalently attached at the cell surface. Although members of this family follow the same general structural pattern as other GPCRs, they differ in that they are characterized by an extremely long N-terminus that contains the GPCR autoproteolysis-inducing (GAIN) domain, which encompasses the highly conserved GPCR proteolytic site (GPS). The aGPCRs are further subdivided into nine groups based on phylogenetic analysis of the 7-transmembrane domain (7TM). Adhesion GPCRs (aGPCRs) are the second largest of the five GPCR families, with 33 and 31 members in humans and mice, respectively. In humans, more than 800 genes encoding different GPCRs have been identified and phylogenetically divided into five discrete families: glutamate, rhodopsin, adhesion, frizzled/taste2, and secretin ( GRAFS classification). The G protein-coupled receptor (GPCR) superfamily comprises the largest class of cell membrane receptors found in metazoan proteomes. The zebrafish aGPCR repertoire, classification, and nomenclature, together with their expression profiles during development and in adult tissues, provides a crucial foundation for elucidating aGPCR functions and pursuing aGPCRs as therapeutic targets. Our results support the notion that zebrafish are a potentially useful model to study the biology of aGPCRs from a functional perspective. Importantly, expression profiles of zebrafish aGPCRs in adult tissues are similar to those previously reported in mouse, rat, and human, underscoring the evolutionary conservation of this family, and therefore the utility of the zebrafish for studying aGPCR biology. Using quantitative real-time PCR, we have defined the expression profiles of 59 zebrafish aGPCRs at 12 developmental time points and 10 adult tissues representing every major organ system.
Phylogenetic analysis suggests that most zebrafish aGPCRs cluster closely with their mammalian homologs, with the exception of three zebrafish-specific expansion events in Groups II, VI, and VIII.
We find that several aGPCRs in zebrafish have multiple paralogs, in line with the teleost-specific genome duplication.
Here, we report that there are at least 59 aGPCRs in zebrafish that represent homologs of 24 of the 33 aGPCRs found in humans compared to humans, zebrafish lack clear homologs of GPR110, GPR111, GPR114, GPR115, GPR116, EMR1, EMR2, EMR3, and EMR4.
Additionally, the expression profiles of the aGPCR family have never been extensively characterized over a developmental time-course in any species. However, aGPCR repertoires have not been defined in any fish species, nor are aGPCR expression profiles in adult tissues known. Zebrafish have proven to be a very effective model for studying the biological functions of aGPCRs in both developmental and adult contexts. Adhesion G protein-coupled receptors (aGPCRs) are the second largest of the five GPCR families and are essential for a wide variety of physiological processes.
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