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

Abstract

The adhesion G protein-coupled receptors latrophilins have been in the limelight for more than 20 years since their discovery as calcium-independent receptors for α-latrotoxin, a spider venom toxin with potent activity directed at neurotransmitter release from a variety of synapse types. Latrophilins are highly expressed in the nervous system. Although a substantial amount of studies has been conducted to describe the role of latrophilins in the toxin-mediated action, the recent identification of endogenous ligands for these receptors helped confirm their function as mediators of adhesion events. Here we hypothesize a role for latrophilins in inter-neuronal contacts and the formation of neuronal networks and we review the most recent information on their role in neurons. We explore molecular, cellular and behavioral aspects related to latrophilin adhesion function in mice, zebrafish, Drosophila melanogaster and Caenorhabditis elegans, in physiological and pathophysiological conditions, including autism spectrum, bipolar, attention deficit and hyperactivity and substance use disorders.

Keywords: actin cytoskeleton; adhesion G protein-coupled receptors; alternative splicing; cell adhesion molecules; latrophilin; neuronal synapse; psychiatric disorders; teneurin.

FIGURE 1

Latrophilin-ligands pairings at the mammalian synapse. Representation of a mammalian mature synaptic formation with pre- and post-synaptic compartments schematized. (A–D) Molecular complexes are shown between latrophilins and indicated ligands in dedicated zoomed-in boxes. (E,F) Components of excitatory synapses are shown such as N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), PSD95, SHANK, Cortactin, MINT, CASK, voltage-dependent calcium channel α. (D–F) Indicated domains are the following: LNS, laminin, neurexin and sex-hormone binding; EGF, epidermal growth factor; TM, transmembrane; PDZ B.M., PSD95, Dlg, Zona occludens binding domain; Lec, Lectin; Olf, Olfactomedin; S/T, serine-threonine rich; Horm, hormone binding; GAIN, GPCR autoproteolysis inducing; Tox, Toxin; FN/FnIII, fibronectin type III; LRR/LR, Leucine-rich repeats; SH3, Src homology 3; GUK, guanylate kinase; CamK, Ca²⁺-Calmodulin kinase; PRO, proline rich; SAM, SH3 and multiple ankyrin repeat; PTB, phosphotyrosine binding; ATD, amino-terminal domain; VFT, Venus fly trap; CRD, cysteine rich domain.

FIGURE 2

Signaling pathways underlying the potential involvement of latrophilins in growth cone and actin structures formation. Representation of growth cone structures and associated signaling. (A) Lamellipodia Formation: GPCR activation leads to their coupling with G proteins provoking subunits dissociation. Activation of the Rac pathway by Gβγ subunits results in the recruitment of WAVE and ARP2/3 complexes at the front of migration and generates actin polymerization (Lowery and Van Vactor, 2009; Chia et al., 2013). The reported interaction between Lphn1 and SHANK could presumptively couple the aGPCR to the actin cytoskeleton (Tobaben et al., 2000). (B) Filipodia Formation: Activation of G proteins by GPCR stimulation at the migration front leads to dissociation of α subunits from βγ subunits, which will in turn activate small GTPase Cdc42 recruiting n-WASP and ARP2/3 complexes and provoking actin polymerization (Lowery and Van Vactor, 2009). (C) Axonic Cone Formation: Proteolytically cleaved teneurin-2 activates latrophilin leading to Gα_q protein induction of PLC followed by an increase in Ca²⁺ release from the endoplasmic reticulum through IP₃ receptors (Vysokov et al., 2018). Alternatively, cAMP levels can be modulated by activation of Gαi or Gαs proteins (yellow) (Muller et al., 2015; Nazarko et al., 2018). In parallel, G protein activation can also lead to the stimulation RhoA/ROCK pathway supporting filopodial formation through actin stabilization (green) (Siehler, 2009).

FIGURE 3

Alternative splicing events for Lphn1, 2 and 3 in Homo sapiens and Mus musculus. The potential alternative splicing events for Lphn1 (A), Lphn2 (B) and Lphn 3 (C) are shown for H. sapiens and M. musculus. Each red box represents a possible splicing event. Green-red double colored boxes indicate splicing events which are only used to introduce a translation start site and thus cannot be combined within the same isoform, while the added asterisk indicates that these splicing events can alternatively be included as a continuous protein sequence of larger isoforms and can be combined with others of the same color code. The yellow box represents splicing events that are exclusively only present in the short isoforms lacking the Lectin domain. The pink box does not indicate a splicing event but represents the site of a potential alternative promoter sequence within a universally used exon. The Open Reading Frame Change (ORFc) indicates a splicing event present in the Lphn1 of H. Sapiens that alters the reading frame to generate a translation start site. Blue-red double colored boxes represent mutually exclusive splicing events (in the case of Lphn2 and Lphn3) two splicing sites with the same start sequence but which are carried out in different isoforms and are mutually excluding. The dotted lines indicate the common events between isoforms and species. The legend at the bottom indicates the possible consequences of the splicing events. Lec, Lectin domain; Olf, Olfactomedin domain; Horm, Hormone binding domain; GAIN, GPCR Autoproteolytic Inducing domain; GPS, GPCR proteolytic site; 7TM, Seven transmembrane domain; PDZ BD, PDZ binding domain; ICL1, ICL2, ICL3: Intracellular loop 1,2,3. ADGRL1,2,3, Adhesion G Protein-Coupled Receptor Latrophilin-1,2,3. Data were extracted from the NCBI database (www.ncbi.nlm.nih.gov) as well as the Ensembl database (www.ensembl.org). Primary assemblies for Homo sapiens and Mus musculus: GRCh38.p12 and GRCm38.p4. ADGRL1 Homo sapiens (Gene ID: 22859; NC_000019.10 and ENSRNOG00000072071); ADGRL1 Mus musculus (Gene ID: 330814; NC_000074.6 and ENSRNOG00000072071); ADGRL2 Homo sapiens (gene ID: 23266; NC_000001.11 and ENSG00000117114); ADGRL2 Mus musculus (Gene ID: 99633; NC_000069.6 and ENSMUSG00000028184); ADGRL3 Homo sapiens (Gene ID:23284; NC_000004.12 and ENSG00000150471); ADGRL3 Mus musculus (Gene ID: 319387; NC_000071.6 and ENSMUSG00000037605) (National Center for Biotechnology Information, 1988; Zerbino et al., 2018).

FIGURE 4

Expression pattern of lat-1 and teneurin-1 in Caenorhabditis elegans. (A) Expression of teneurin-1a in neurons M1, M2, M4, I3, NSMs of the pharyngeal nervous system (Morck et al., 2010); (B) Expression of lat-1 in pharyngeal and extra-pharyngeal neurons near of terminal bulb and isthmus that belong to the pharyngeal nervous system (1, Corpus; 2, Extra-pharyngeal neurons; 3, Neuron in the terminal bulb; 4, Intestine; 5, Pharyngeal neurons; 6, Neuron in the corpus with projections into the isthmus; 7, Isthmus; 8, Terminal bulb; 9, Pharyngeal-intestinal valve) (Willson et al., 2004; Langenhan et al., 2009); (C) Expression of lat-1 in muscle cell membrane of the pharynx (Promel et al., 2012); (D) Representation of epidermoblast during dorsal intercalation. ten-1 expressed in Cpaaaa and Caaa lineages, while lat-1 expression is restricted to Caaa lineages (Promel et al., 2012); (E) Expression of lat-1 in excretory cells and neurons of the nerve ring (1, Sensory dentrites; 2, Nerve ring; 3, Dorsal nerve cord; 4, Excretory cells; 5, Ventral nerve cord) (Willson et al., 2004; Langenhan et al., 2009; Promel et al., 2012); (F) representation of the expression of lat-1 in gonads of an adult hermaphrodite (Langenhan et al., 2009; Promel et al., 2012). Pm: Pharyngeal muscle, NSMs: neurosecretory motor sensory. Images were adapted with the permission of Wormatlas (www.wormatlas.org).

FIGURE 5

Expression pattern of dCirl and its possible ligand Ten-m in Drosophila melanogaster (fruit fly). (A) Expression of dCirl and Ten-m during the larval stage. A′) Schematic representation of the central nervous system indicating the reported expression of dCirl in the ganglion of the ventral nerve cord (in green) (Scholz et al., 2015). A″, A″″) Magnified representation of the sensory neurons in the pentascolopidial chordotonal organs (lch5) showing the reported expression pattern of dCirl in the dendritic membrane and the single cilium of chordotonal (ChO) neurons (in green) (Scholz et al., 2015). A″′) Fluorescence microscopy image showing Ten-m promoter-driven expression of YFP in the scolopale cells of the lch5 (in green). (B) Expression of dCirl and Ten-m during the adult stage. B′) Coronal view representation of the adult brain depicting dCirl expression in the medulla of the optic system and in the mushroom bodies (in green) (Gehring, 2014). B″) Fluorescence microscopy image showing Ten-m promoter-driven expression of YFP in the optic lobe (in green). B″′) Schematic representation of contacting photoreceptor neurons in the eye expressing Ten-m (in orange) and dCirl (in green) (Gehring, 2014). OL, optic lobe; MB, mushroom body; ME, medulla of the optic system.

FIGURE 6

Expression pattern of Lphn3.1 – Lphn3.2 in Danio rerio (zebrafish). (A) Expression of the two orthologs for lphn3 in zebra fish, both present a similar expression pattern during the larval stage observed in the ventral part of the telencephalon and diencephalon, hindbrain, the posterior brain and the ventral area of the spine (in green) (Lange et al., 2012). (B) Expression in adult zebrafish of Lphn3.1 is shown along the telencephalic midline, telencephalic parenchyma, the anterior thalamus, the periacal ductal gray matter, the superior nucleus of raphe, the periventricular nucleus of the lower hypothalamus, the cerebellum and the nucleus of the medial longitudinal fascicle (green outline) (Lange et al., 2012).

FIGURE 7

Expression pattern of the three isoforms of latrophilins in the central nervous system of Mus musculus. (A) The magnification represents the mid-sagittal section of the brain of M. musculus; (B–D) areas highlighted in purple, red and green show the latrophilin-1, 2, and 3 mRNA or protein expression, respectively. ICTX, Isocortex; HIP, hippocampus; CA, Ammon′s horn; DG, dentate gyrus; HY, hyppothalamus; CP, caudate puntamen; TH, thalamus; IO, inferior olivary; STR, striatum; SNr, substantia nigra pars reticulata; GP, globus pallidus; RSP, retrosplenial cortex; CB, cerebellum, CTXsp, cortical subplate; MB, midbrain; MY, medula; OLF, olfatory areas; PAL, pallidum; P, pons. Protein data were from Anderson et al. (2017). mRNA data were extracted from Kreienkamp et al. (2000), Tobaben et al. (2000) and the Allen Brain Atlas (www.brain-map.org).

FIGURE 8

Molecular networks involving latrophilins and their ligands in human neuropathology. Neurological disorders associated with variations in genes from latrophilins and some of their endogenous ligands. Unless otherwise stated in the text, data were extracted from the GWAS catalog database and Harmonizome database (https://www.ebi.ac.uk/gwas/) (Buniello et al., 2019) and (http://amp.pharm.mssm.edu/Harmonizome/). ADHD, Attention Deficit Hyperactivity Disorder; ASD, Autism spectrum disorder; BD, Bipolar disorder; SUD, Substance use disorder; SCZ, Schizophrenia; MCP, microcephaly; RES, rhombencephalosynapsis.