Convergent selective signaling impairment exposes the pathogenicity of latrophilin-3 missense variants linked to inheritable ADHD susceptibility.

Latrophilin-3 (Lphn3; also known as ADGRL3) is a member of the adhesion G Protein Coupled Receptor subfamily, which participates in the stabilization and maintenance of neuronal networks by mediating intercellular adhesion through heterophilic interactions with transmembrane ligands. Polymorphisms modifying the Lphn3 gene are associated with attention-deficit/hyperactivity disorder (ADHD) in children and its persistence into adulthood. How these genetic alterations affect receptor function remains unknown. Here, we conducted the functional validation of distinct ADHD-related Lphn3 variants bearing mutations in the receptor's adhesion motif-containing extracellular region. We found that all variants tested disrupted the ability of Lphn3 to stabilize intercellular adhesion in a manner that was distinct between ligands classes, but which did not depend on ligand-receptor interaction parameters, thus pointing to altered intrinsic receptor signaling properties. Using G protein signaling biosensors, we determined that Lphn3 couples to Gαi1, Gαi2, Gαs, Gαq, and Gα13. However, all ADHD-related receptor variants consistently lacked intrinsic as well as ligand-dependent Gα13 coupling efficiency while maintaining unaltered coupling to Gαi, Gαs, and Gαq. Consistent with these alterations, actin remodeling functions as well as actin-relevant RhoA signaling normally displayed by the constitutively active Lphn3 receptor were impeded by select receptor variants, thus supporting additional signaling defects. Taken together, our data point to Gα13 selective signaling impairments as representing a disease-relevant pathogenicity pathway that can be inherited through Lphn3 gene polymorphisms. This study highlights the intricate interplay between Lphn3 GPCR functions and the actin cytoskeleton in modulating neurodevelopmental cues related to ADHD etiology.

A Review of Botanical Extracts with Repellent and Insecticidal Activity and Their Suitability for Managing Mosquito-Borne Disease Risk in Mexico.

Among the main arboviruses affecting public health in tropical regions are dengue, zika, and chikungunya, transmitted mainly by mosquitoes of the Aedes genus, especially Aedes aegypti. In recent years, outbreaks have posed major challenges to global health, highlighting the need for integrated and innovative strategies for their control and prevention. Prevention strategies include the elimination of vectors and avoiding mosquito bites; this can be achieved through the use of bioinsecticides and repellents based on plant phytochemicals, as they offer sustainable, ecological, and low-cost alternatives. Mexico has a variety of plants from which both extracts and essential oils have been obtained which have demonstrated significant efficacy in repelling and/or killing insect vectors. This review examines the current knowledge on plant species found in Mexico which are promising options concerning synthetic compounds in terms of their repellent and insecticidal properties against mosquitoes of the genus Aedes and that are friendly to the environment and health.

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

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.