Latrophilins updated

Abstract

Latrophilins (LPHN) are part of a yet unexplored family of receptors comprising three isoforms, LPHN1-3, and belonging to a unique branch of G protein-coupled receptors (GPCR) named adhesion GPCR (aGPCR). LPHN are considered to be prototypical models for the study of aGPCR as they are one of the most evolutionary conserved members. Previously described as the target for a potent neurotoxin from the black widow spider venom, LPHN are now being studied under a whole new perspective. Indeed, recent advances have provided a better understanding of different aspects of this prototypical family of receptors: 1) elucidation of LPHN ectodomain organization by crystallography has unveiled a new functional domain with great repercussion on all the other members of the aGPCR family, 2) proteomic approaches have opened the gate to unsuspected functional characteristics of LPHN cellular role, and 3) genetic approaches have provided hints into the physiological functions of LPHN in specific systems and organisms. Moreover, genomic linkage studies screening human patients from diverse genetic backgrounds have involved LPHN gene defects in human disorders such as attention-deficit hyperactivity disorder and cancer. In this review, we will provide a historical perspective addressing experimental research on these receptors while highlighting the new advances and discoveries concerning LPHN functions. As GPCR still represent the most studied targets for the development of pharmacological approaches aiming at alleviating human disorders, the relevance of studying LPHN retains a high pertinence to better understand these receptors for the treatment of human diseases.

Adhesion G Protein–Coupled Receptors as Drug Targets

“…The latrophilins/ADGRL1-3 and BAIs/ADGRB1-3 appear to be critical for synapse formation and strengthening. ADGRL1-3 receptors are found in both pre-and post-synaptic compartments (103). Human studies have linked ADGRL3 to attention deficit hyperactivity disorder (ADHD) (104; 105) and animal studies have supported this finding.…”

CYP4BN6 and CYP6BQ11 mediate insecticide susceptibility and their expression is regulated by Latrophilin in Tribolium castaneum

“…Large‐scale RNAi screening has identified 25 GPCRs that could potentially be novel insecticide targets based on the fact that knockdown of these GPCRs results in more than 30% mortality in T. castaneum . One of the identified GPCRs is latrophilin ( lph ), which was previously described as the target of a potent α‐latrotoxin from black widow spider venom . We discovered that Tclph mRNA is highly expressed in the central nervous system (CNS) of T. castaneum .…”

“…38,44 One of the identified GPCRs is latrophilin (lph), which was previously described as the target of a potent -latrotoxin from black widow spider venom. 45 We discovered that Tclph mRNA is highly expressed in the central nervous system (CNS) of T. castaneum. 46 Additionally, our latest studies further showed that the transcripts of Tclph are dramatically induced by dichlorvos (an organophosphorus insecticide) and carbofuran (a carbamate insecticide), two key anticholinesterase insecticides that kill insects through overstimulation of the nervous system; knockdown of Tclph also significantly enhanced the susceptibility of the larvae to these two insecticides.…”

C‐terminal phosphorylation of latrophilin‐1/ADGRL1 affects the interaction between its fragments

“…). Possible phosphorylation of LPHN1 has been previously mentioned in several reviews, including a very comprehensive literature analysis, but, to our knowledge, never experimentally addressed (except using MS2‐based predictions, see below). However, phosphorylation of GPCRs is very important for their functions and, therefore, deserves an in‐depth investigation.…”