Involvement of the Adhesion GPCRs Latrophilins in the Regulation of Insulin Release

Röthe, Juliane; Thor, Doreen; Winkler, Jana Barbro; Knierim, Alexander Bernd; Binder, Claudia R.; Huth, Sandra; Kraft, Robert A.; Rothemund, Sven; Schöneberg, Torsten; Prömel, Simone

doi:10.1016/j.celrep.2019.01.040

Cited by 52 publications

(44 citation statements)

References 59 publications

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“…Fifth, a revised aGPCR nomenclature should consider the expected multitude of aGPCR transcript variants. Recent studies have already highlighted that numerous variants are derived from single aGPCR genes by alternative promoters and splicing …”

Section: Discussionmentioning

confidence: 99%

Revisiting the classification of adhesion GPCRs

Scholz

Langenhan

Schöneberg

2019

Annals of the New York Academy of Sciences

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G protein–coupled receptors (GPCRs) are encoded by over 800 genes in the human genome. Motivated by different scientific rationales, the two classification systems that are mainly in use, the ABC and GRAFS systems, organize GPCRs according to their pharmacological features and phylogenetic relations, respectively. Within those systems, adhesion GPCRs (aGPCRs) constitute a group of over 30 mammalian homologs, most of which are still orphans with undefined activating signals and signal transduction properties. Previous efforts have further subdivided mammalian aGPCRs into nine subfamilies to indicate phylogenetic relationships. However, this subclassification scheme has shortcomings and inconsistencies that require attention. Here, we have reassessed the phylogenetic relationships of aGPCRs from vertebrate and invertebrate species. Our findings confirm that secretin receptor–like GPCRs most probably emerged from ancestral aGPCRs. We show that reassignment of several aGPCRs to families essentially requires input from functional data. Our analyses establish the need for introducing novel aGPCR subfamilies due to aGPCR sequences from invertebrate species that are not readily assignable to any existing subfamily. We conclude that the current classification systems ought to be updated to consider an unambiguous taxonomy of a hierarchically organized classification and pharmacological properties, and to accommodate phylogenetic affiliations between aGPCR genes within mammals and across the animal kingdom.

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Section: Discussionmentioning

confidence: 99%

Revisiting the classification of adhesion GPCRs

Scholz

Langenhan

Schöneberg

2019

Annals of the New York Academy of Sciences

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“…Transcripts from latrophilin genes are prone to multiple alternative splicing events. In mammals, each isoform (LPHN1, 2, and 3) possesses distinct splicing events, resulting in a level of diversity that does not follow the rules of redundancy, especially when analyzing the receptors’ intracellular interface . Indeed, the intracellular splicing events differentially target the third intracellular loop and the cytoplasmic tail for each isoform.…”

Section: Discussionmentioning

confidence: 99%

“…Latrophilin‐1 (ADGRL1/LPHN1), a member of the adhesion G protein–coupled receptor (aGPCR) family, is mainly expressed in brain, but can also be found in various other tissues . The preferential presence of LPHN1 in neurons is highly suggestive of a function related to synapses, although not exclusively.…”

Section: Introductionmentioning

confidence: 99%

Alternative splicing event modifying ADGRL1/latrophilin‐1 cytoplasmic tail promotes both opposing and dual cAMP signaling pathways

Ovando-Zambrano

Arias‐Montaño

Boucard³

2019

Annals of the New York Academy of Sciences

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The adhesion G protein–coupled receptor ADGRL1/latrophilin‐1 (LPHN1) stabilizes synapse formation through heterophilic interactions. A growing consensus is pointing to the role of LPHN1 in modulating intracellular levels of cAMP, although conflicting data exist. Variants of LPHN1 resulting from alternative splicing differ at multiple sites, two of which, designated as SSA and SSB, modify extracellular and intracellular receptor regions, respectively. While SSA splicing modulates receptor–ligand affinity, the function of SSB splicing remains elusive. Here, we explored the role of SSB in an attempt to unify current findings on LPHN1 signaling pathways by testing SSB‐containing and SSB‐deficient receptor variants in signaling paradigms involving interaction with their ligands neurexin and FLRT. cAMP competitive binding assays revealed that cells expressing either receptor variant exhibited a ligand‐dependent decrease in the forskolin‐induced cAMP accumulation. Surprisingly, the expression of SSB‐containing LPHN1 promoted both constitutive and ligand‐dependent cAMP production, whereas SSB‐deficient LPHN1 did not. Pertussis toxin treatment unveiled a constitutive coupling to Gαi/o for SSB‐containing LPHN1 while abrogating the ligand‐mediated activation of Gαs. Importantly, neither receptor variant increased the intracellular concentration of Ca2+ nor MAP kinase activation in the presence of ligands. These results suggest that SSB splicing selectively affects the duality of LPHN1 signaling toward opposing cAMP pathways.

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“…So haben gewebespezifische Spleißvarianten der Latrophiline aus Gehirn und pankreatischen Inseln jeweils unterschiedliches Signalverhalten. 18,19) Das Spleißverhalten bedingt wohl auch den modularen Aufbau von aGPCRs.…”

Section: Adhäsions-gpcr -Hindernisse Und Perspektivenunclassified