Latrophilins: A Neuro-Centric View of an Evolutionary Conserved Adhesion G Protein-Coupled Receptor Subfamily

Moreno-Salinas, Ana L.; Avila-Zozaya, Monserrat; Ugalde-Silva, Paul; Hernández-Guzmán, David A.; Missirlis, Fanis; Boucard, Antony A.

doi:10.3389/fnins.2019.00700

Cited by 41 publications

(39 citation statements)

References 190 publications

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“…Insights into AGPCR activation mechanisms may be gleaned from the endogenous ligands that target them, some of which were introduced previously. Wide-ranging de-orphanization studies have uncovered several endogenous ligands that bind to individual AGPCRs (reviewed in (29)(30)(31)33,35,111,112)). The identities of the ligands provide useful clues for understanding receptor activation mechanisms in physiological contexts.…”

Section: How Do Agpcr Ligands Modulate Receptor Activity?mentioning

confidence: 99%

“…Most ADGRL receptors (ADGRL1-4), excluding ADGRL4, are localized on axons, axonal growth cones and nerve terminals (78,(112)(113)(114). They are structurally distinguished from other AGPCRs by the presence of an N-terminal olfactomedin (Olf) domain and a lectin-like (Lec) domain.…”

Section: Trans-cell-presented Proteinsmentioning

confidence: 99%

“…These neuronal reshaping processes are thought to result from Rho / Rac-mediated actin cytoskeletal changes downstream of G12/13 signaling, through which ADGRL3 was recently shown to signal (122)(123)(124)(125)(126)(127)(128). ADGRLs also couple to Gi/o and Gq, which may also influence neuronal migration and synaptogenesis, as the asymmetric production of cAMP or Ca 2+ within the cell influences growth cone guidance (112,(129)(130)(131)(132).…”

Section: Trans-cell-presented Proteinsmentioning

confidence: 99%

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Mechanisms of adhesion G protein–coupled receptor activation

Vizurraga

Adhikari

Yeung

et al. 2020

Journal of Biological Chemistry

114

141

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Adhesion G protein coupled receptors (AGPCRs) are a thirty-three-member subfamily of Class B GPCRs that control a wide array of physiological processes and are implicated in disease. AGPCRs uniquely contain large, self-proteolyzing extracellular regions that range from hundreds to thousands of residues in length. AGPCR autoproteolysis occurs within the extracellular GPCR Autoproteolysis-Inducing (GAIN) domain that is proximal to the N-terminus of the G protein-coupling seven transmembrane spanning (7TM) bundle. GAIN domain-mediated self-cleavage is constitutive and produces two-fragment holoreceptors that remain bound at the cell surface. It has been of recent interest to understand how AGPCRs are activated in relation to their two-fragment topologies. Dissociation of the AGPCR fragments stimulates G protein signaling through the action of the tethered-peptide-agonist stalk that is occluded within the GAIN domain in the holoreceptor form. AGPCRs can also signal independently of fragment dissociation, and a few receptors possess GAIN domains incapable of self-proteolysis. This has resulted in complex theories as to how these receptors are activated in vivo, complicating pharmacological advances. Currently there is no existing structure of an activated AGPCR to support any of the theories. Further confounding AGPCR research is that many of the receptors remain orphans and lack identified activating ligands. In this review, we provide a detailed layout of the current theorized modes of AGPCR activation with discussion of potential parallels to mechanisms used by other GPCR classes. We provide a classification means for the ligands that have been identified and discuss how these ligands may activate AGPCRs in physiological-contexts.

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Section: How Do Agpcr Ligands Modulate Receptor Activity?mentioning

confidence: 99%

Section: Trans-cell-presented Proteinsmentioning

confidence: 99%

Section: Trans-cell-presented Proteinsmentioning

confidence: 99%

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Mechanisms of adhesion G protein–coupled receptor activation

Vizurraga

Adhikari

Yeung

et al. 2020

Journal of Biological Chemistry

114

141

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“…LPHNs have been hypothesized to mediate mechanotransduction in neurons 30 , though mechanistic insight is lacking. It is notable that, while LPHNs have been studied almost exclusively in the brain 31…”

Section: Discussionmentioning

confidence: 99%

Latrophilins are essential for endothelial junctional fluid shear stress mechanotransduction

Tanaka

Prendergast

Hintzen

et al. 2020

Preprint

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Endothelial cell (EC) responses to fluid shear stress (FSS) are crucial for vascular development, adult physiology and disease. PECAM1 is an important transducer but earlier events remain poorly understood. We therefore investigated heterotrimeric G proteins in FSS sensing.Knockdown (KD) in ECs of single Gα proteins had little effect but combined depletion of Gαi and Gαq/11 blocked all known PECAM1-dependent responses. Re-expression of Gαi2 and Gαq but not Gαi1 and Gαi3 rescued these effects. Sequence alignment and mutational studies identified that K307 in Gαi2 and Gq/11 (Q306 in Gαi1/3), determines participation in flow signaling. We developed pull-down assays for measuring Gα activation and found that this residue, localized to the GPCR interface, determines activation by FSS. We developed a protocol for affinity purification of GPCRs on activated Gα's, which identified latrophilins (ADGRLs) as specific upstream interactors for Gαi2 and Gq/11. Depletion of latrophilin-2 blocked EC activation of Gαi2 and Gαq, downstream events in vitro, and flow-dependent vascular morphogenesis in zebrafish embryos. Surprisingly, latrophilin-2 depletion also blocked flow activation of two additional pathways activated at cell-cell junctions, Smad1/5 and Notch1, independently of Gα proteins.Latrophilins are thus central mediators of junctional shear stress mechanotransduction via Gα protein-dependent and -independent mechanisms.

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“…Increased Caspase-3 immunoreactivity was also observed in the Cntn6-deficient visual cortex ( Zuko et al, 2016a ). Interestingly, Lphn1 is known to interact with Neurexin-1, another neuronal IgCAM whose disruption is also associated with ASD ( Kim et al, 2008 ; Moreno-Salinas et al, 2019 ). These interactions between Lphn1, Cntn6, and other neuronal IgCAMs may point toward a common cellular pathway implicated in ASD etiology.…”

Section: Neurophysiological Roles Of Chl1 Cntn6 mentioning

confidence: 99%

Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion Syndrome and Autism Spectrum Disorder

Gandawijaya

Bamford

Burbach

et al. 2021

Front. Cell. Neurosci.

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Autism spectrum disorder (ASD) is characterized by impaired social interaction, language delay and repetitive or restrictive behaviors. With increasing prevalence, ASD is currently estimated to affect 0.5–2.0% of the global population. However, its etiology remains unclear due to high genetic and phenotypic heterogeneity. Copy number variations (CNVs) are implicated in several forms of syndromic ASD and have been demonstrated to contribute toward ASD development by altering gene dosage and expression. Increasing evidence points toward the p-arm of chromosome 3 (chromosome 3p) as an ASD risk locus. Deletions occurring at chromosome 3p result in 3p-deletion syndrome (Del3p), a rare genetic disorder characterized by developmental delay, intellectual disability, facial dysmorphisms and often, ASD or ASD-associated behaviors. Therefore, we hypothesize that overlapping molecular mechanisms underlie the pathogenesis of Del3p and ASD. To investigate which genes encoded in chromosome 3p could contribute toward Del3p and ASD, we performed a comprehensive literature review and collated reports investigating the phenotypes of individuals with chromosome 3p CNVs. We observe that high frequencies of CNVs occur in the 3p26.3 region, the terminal cytoband of chromosome 3p. This suggests that CNVs disrupting genes encoded within the 3p26.3 region are likely to contribute toward the neurodevelopmental phenotypes observed in individuals affected by Del3p. The 3p26.3 region contains three consecutive genes encoding closely related neuronal immunoglobulin cell adhesion molecules (IgCAMs): Close Homolog of L1 (CHL1), Contactin-6 (CNTN6), and Contactin-4 (CNTN4). CNVs disrupting these neuronal IgCAMs may contribute toward ASD phenotypes as they have been associated with key roles in neurodevelopment. CHL1, CNTN6, and CNTN4 have been observed to promote neurogenesis and neuronal survival, and regulate neuritogenesis and synaptic function. Furthermore, there is evidence that these neuronal IgCAMs possess overlapping interactomes and participate in common signaling pathways regulating axon guidance. Notably, mouse models deficient for these neuronal IgCAMs do not display strong deficits in axonal migration or behavioral phenotypes, which is in contrast to the pronounced defects in neuritogenesis and axon guidance observed in vitro. This suggests that when CHL1, CNTN6, or CNTN4 function is disrupted by CNVs, other neuronal IgCAMs may suppress behavioral phenotypes by compensating for the loss of function.

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Latrophilins: A Neuro-Centric View of an Evolutionary Conserved Adhesion G Protein-Coupled Receptor Subfamily

Cited by 41 publications

References 190 publications

Mechanisms of adhesion G protein–coupled receptor activation

Mechanisms of adhesion G protein–coupled receptor activation

Latrophilins are essential for endothelial junctional fluid shear stress mechanotransduction

Cell Adhesion Molecules Involved in Neurodevelopmental Pathways Implicated in 3p-Deletion Syndrome and Autism Spectrum Disorder

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