InteractiveFly: GeneBrief

Calcium-independent receptor for α-latrotoxin: Biological Overview | References

BIOLOGICAL OVERVIEW

G-protein-coupled receptors (GPCRs) are typically regarded as chemosensors that control cellular states in response to soluble extracellular cues. However, the modality of stimuli recognized through adhesion GPCR (aGPCR), the second largest class of the GPCR superfamily, is unresolved. This study study characterizes the Drosophila aGPCR Latrophilin/dCirl, a prototype member of this enigmatic receptor class. dCirl is shown to shapes the perception of tactile, proprioceptive, and auditory stimuli through chordotonal neurons, the principal mechanosensors of Drosophila. dCirl sensitizes these neurons for the detection of mechanical stimulation by amplifying their input-output function. These results indicate that aGPCR may generally process and modulate the perception of mechanical signals, linking these important stimuli to the sensory canon of the GPCR superfamily (Scholz, 2015).

Because of the nature of their activating agents, G-protein-coupled receptors (GPCRs) are established sensors of chemical compounds. The concept that GPCRs may also be fit to detect and transduce physical modalities, i.e., mechanical stimulation, has received minor support thus far. In vitro observations showed that, in addition to classical soluble agonists, mechanical impact such as stretch, osmolarity, and plasma membrane viscosity may alter the metabotropic activity of individual class A GPCR. However, the ratio and relationship between chemical and mechanical sensitivity and the physiological role of the latter remain unclear (Scholz, 2015).

Genetic studies have indicated that adhesion GPCRs (aGPCRs), a large GPCR class with more than 30 mammalian members, are essential components in developmental processes (Langenhan, 2009). Human mutations in aGPCR loci are notoriously linked to pathological conditions emanating from dysfunction of these underlying mechanisms, including disorders of the nervous and cardiovascular systems, and neoplasias of all major tissues (Langenhan, 2013). However, as the identity of aGPCR stimuli is unclear, it has proven difficult to comprehend how a GPCRs exert physiological control during these processes (Scholz, 2015).

Latrophilins constitute a prototype aGPCR subfamily because of their long evolutionary history. Latrophilins are present in invertebrate and vertebrate animals (Fredriksson, 2005), and their receptor architecture has remained highly conserved across this large phylogenetic distance. The mammalian Latrophilin 1 homolog was identified through its capacity to bind the black widow spider venom component α-latrotoxin, which induces a surge of vesicular release from synaptic terminals and neuroendocrine cells through formation of membrane pores. Latrophilin 1/ADGRL1 was suggested to partake in presynaptic calcium homeostasis by interacting with a teneurin ligand (Silva, 2011) and in trans-cellular adhesion through interaction with neurexins 1b and 2b (Boucard, 2012). Further, engagement of Latrophilin 3/ADGRL3 with FLRT proteins may contribute to synapse development (O'Sullivan, 2014). The role of Latrophilins in the nervous system thus appears complex (Scholz, 2015).

This study has used a genomic engineering approach to remove and modify the Latrophilin locus dCirl, the only Latrophilin homolog of Drosophila melanogaster. dCirl was shown to be required in chordotonal neurons for adequate sensitivity to gentle touch, sound, and proprioceptive feedback during larval locomotion. This indicates an unexpected role of the aGPCR Latrophilin in the recognition of mechanosensory stimuli and provides a unique in vivo demonstration of a GPCR in mechanoception (Scholz, 2015).

This analysis provides multiple lines of evidence to support that Latrophilin/dCirl, one of only two aGPCRs in the fly, is a critical regulator of mechanosensation through chordotonal neurons in Drosophila larvae. Larval chordotonal organs respond to tactile stimuli arising through gentle touch, mechanical deformation of the larval body wall and musculature during the locomotion cycle, and vibrational cues elicited through sound. First, this study determined that registration of all these mechanical qualities is reduced in the absence of dCirl, based on behavioral assays. Then it was established that behavioral defects can be rescued by re-expression of dCirl in chordotonal neurons, one of several cell types with endogenous dCirl expression. Mechanically stimulated lch5 neurons lacking dCirl were shown to responded with action currents at approximately half the control rate across a broad spectrum of stimulation frequencies, providing direct functional evidence for a role of dCirl in chordotonal dendrites, the site of mechanotransduction and receptor potential generation, or somata, where action potentials are likely initiated. Further, the ability of chordotonal neurons to generate mechanical responses relative to their background spike activity appears to be modulated by dCirl (Scholz, 2015).

Combining dCirl KO with strong hypomorphs of trp homologs, ion channels that are directly responsible for the conversion of mechanical stimulation into electrical signals within chordotonal neurons, implied that dCirl operates upstream of them. Intriguingly, removing dCirl from nompC or nan mutant backgrounds resulted in inverse outcomes, i.e., decreased and increased crawling distances, respectively. This suggests that dCirl enhances nompC activity while curtailing nan function. These experiments demonstrate that dCirl genetically interacts with essential elements of the mechanotransduction machinery in chordotonal cilia. Additional studies showed that the dCirl promoter contains a RFX/Fd3F transcription factor signature that implicates dCirl in the mechanosensitive specialization of sensory cilia (Newton, 2012). On the basis of these results, it is proposed that dCirl partakes in the process of mechanotransduction or spike initiation and transmission to promote sensory encoding (Scholz, 2015).

The classical model of GPCR activation has become the archetypical example for cellular perception of external signals. It comprises soluble ligands that bind to the extracellular portions of a cognate receptor, whereby receptor conformation is stabilized in a state that stimulates metabotropic effectors. Thus, GPCRs are primarily regarded as chemosensors due to the nature of their activating agents. The concept that GPCRs may also be fit to detect and transduce physical modalities, i.e., mechanical stimulation, has received little support thus far (Scholz, 2015).

aGPCRs display an exceptional property among the GPCR superfamily in that they recognize cellular or matricellular ligands. To date, only one ligand, Type 4 collagen, has proved adequate to induce intracellular signaling (Paavola, 2014), whereas for the vast majority of ligand-aGPCR interactions this proof either failed or is lacking (Langenhan, 2013). This implies that sole ligand recognition is generally not sufficient to induce a metabotropic response of aGPCRs. Thus, in addition to ligand engagement, the current results suggest that mechanical load is a co-requirement to trigger the activity of dCIRL, a prototypical aGPCR homolog (Scholz, 2015).

Recent findings place aGPCRs in the context of mechanically governed cellular functions (Yang, 2013), but how mechanical perception through aGPCR activity impinges on cell responses has not yet been established. In addition, the molecular structure of aGPCR is marked by the presence of a GPCR auto-proteolysis inducing (GAIN) domain (Arac, 2012), which plays a paramount role in signaling scenarios for aGPCRs (Promel, 2013). This domain type is also present in PKD-1/Polycystin-1-like proteins, which are required to sense osmotic stress and fluid flow in different cell types and are thus considered bona fide mechanosensors (Retailleau, 2014). In addition, studies on EGF-TM7-, BAI-, and GPR56-type aGPCRs further showed that proteolytic processing and loss of NTF may figure prominently in activation of the receptors' metabotropic signaling output and that mechanical forces exerted through receptor-ligand contact are required for receptor internalization (Scholz, 2015 and references therein).

dCirl is not the only aGPCR associated with mechanosensation. Celsr1 is required during planar cell polarity establishment of neurons of the inner ear sensory epithelium. Similarly, the very large G-protein-coupled receptor 1 (VLGR1) exerts an ill-defined developmental role in cochlear inner and outer hair cells, where the receptor connects the ankle regions of neighboring stereocilia. In addition, VLGR1 forms fibrous links between ciliary and apical inner segment membranes in photoreceptors. Both cell types are affected in a type of Usher syndrome, a congenital combination of deafness and progressive retinitis pigmentosa in humans, which is caused by loss of VLGR1 function. Although present evidence derived from studies of constitutively inactive alleles suggests a requirement for Celsr1 and VLGR1 aGPCR for sensory neuron development, their putative physiological roles after completion of tissue differ-entiation have remained unclear and should be of great interest (Scholz, 2015 and references therein).

In the current model on dCirl function, aGPCR activity, adjusted by mechanical challenge, modulates the molecular machinery gating mechanotransduction currents or the subsequent initiation of action potentials and ensures that mechanical signals are encoded distinctly from the background activity of the sen-sory organ. Thereby, dCirl shapes amplitude and kinetics of the sensory neuronal response. Linking adequate physiological receptor stimulation to downstream pathways and cell function is an essential next step to grasp the significance of aGPCR function and the consequences of their malfunction in human conditions. The versatility of the dCirl model now provides an unprecedented opportunity to study the mechanosensory properties of an exemplary aGPCR and to uncover features that might prove of general relevance for the function and regulation of the entire aGPCR class (Scholz, 2015).

Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons

Adhesion-type G protein-coupled receptors (aGPCRs), a large molecule family with over 30 members in humans, operate in organ development, brain function and govern immunological responses. Correspondingly, this receptor family is linked to a multitude of diverse human diseases. aGPCRs have been suggested to possess mechanosensory properties, though their mechanism of action is fully unknown. This study shows that the Drosophila aGPCR Latrophilin/dCIRL acts in mechanosensory neurons by modulating ionotropic receptor currents, the initiating step of cellular mechanosensation. This process depends on the length of the extended ectodomain and the tethered agonist of the receptor, but not on its autoproteolysis, a characteristic biochemical feature of the aGPCR family. Intracellularly, dCIRL quenches cAMP levels upon mechanical activation thereby specifically increasing the mechanosensitivity of neurons. These results provide direct evidence that the aGPCR dCIRL acts as a molecular sensor and signal transducer that detects and converts mechanical stimuli into a metabotropic response (Scholz, 2017).

This study demonstrates how a GPCR can specifically shape mechanotransduction in a sensory neuron in vivo. This study thus serves a two-fold purpose. It delineates pivotal steps in the activation paradigm of aGPCRs and sheds light on the contribution of metabotropic signals to the physiology of neuronal mechanosensation (Scholz, 2017).

While there is ongoing discussion whether metabotropic pathways are suitable to sense physical or chemical stimuli with fast onset kinetics, due to the supposed inherent slowness of second messenger systems, the results demonstrate that the aGPCR dCIRL/Latrophilin is necessary for faithful mechanostimulus detection in the lch5 organ of Drosophila larvae. In these PNS neurons, dCIRL contributes to the correct setting of the neuron's mechanically-evoked receptor potential. This is in line with the location of the receptor, which is present in the dendritic membrane and the single cilium of chordotonal organ (ChO) neurons, one of the few documentations of the subcellular location of an aGPCR in its natural environment. The dendritic and ciliary membranes harbor mechanosensitive Transient Receptor Potential (TRP) channels that elicit a receptor potential in the mechanosensory neuron by converting mechanical strain into ion flux. Moreover, two mechanosensitive TRP channel subunits, TRPN1/NompC and TRPV/Nanchung, interact genetically with dCirl (Scholz, 2015). The present study further specifies this relationship by showing that the extent of the mechanosensory receptor current is controlled by dCirl. This suggests that the activity of the aGPCR directly modulates ion flux through TRP channels, and highlights that metabotropic and ionotropic signals may cooperate during the rapid sensory processes that underlie primary mechanosensation (Scholz, 2017).

The nature of this cooperation is yet unclear. Second messenger signals may alter force-response properties of ion channels through post-translational modifications to correct for the mechanical setting of sensory structures, e.g. stretch, shape or osmotic state of the neuron, before acute mechanical stimuli arrive. Indeed, there are precedents for such a direct interplay between GPCRs and channel proteins in olfactory and cardiovascular contexts (Scholz, 2017).

ChOs are polymodal sensors that can also detect thermal stimuli. This study shows that dCIRL does not influence this thermosensory response (between 15°C and 30°C) emphasizing the mechano-specific role of this aGPCR. Replacing sensory input by optogenetic stimulation supports this conclusion, since stimulation with ChR2-XXM, a mutant of Channelrhodopsin-2, evoked normal activity in dCirl^KO larvae (Scholz, 2017).

Turning to the molecular mechanisms of dCIRL activation, this study shows that the length of the extracellular tail instructs receptor activity. This observation is compatible with an extracellular engagement of the dCIRL NTF with cellular or matricellular protein(s) through its adhesion domains. Mammalian latrophilins were shown to interact with teneurins, FLRTs and neurexins 1β and 2β suggesting that the receptors are anchored to opposed cell surfaces through their ligands. However, FLRTs do not exist in Drosophila and an engagement of dCIRL with the other two candidate partners could not be detected to date indicating that other interactors may engage and mechanically affix dCIRL. The data support a model where the distance between ligand-receptor contact site and signaling 7TM unit determines the mechanical load onto the receptor protein and its subsequent signal output. This scenario bears similarity to the role of the cytoplasmic ankyrin repeats of NompC, which provide a mechanical tether to the cytoskeleton of mechanosensory cells, and are essential for proper mechanoactivation of this ionotropic sensor (Scholz, 2017).

aGPCR activation occurs by means of a tethered agonist (Stachel) (Liebscher, 2014; Monk, 2015; Stoveken, 2015), which encompasses the last β-strand of the GPCR autoproteolysis-inducing (GAIN) domain. Structural concerns imply that after GAIN domain cleavage a substantial part of the Stachel remains enclosed within the GAIN domain and should thus be inaccessible to interactions with the 7TM domain. These considerations beg the question how the tethered agonist gets exposed to stimulate receptor activity, and how this process relates to the mechanosensitivity of aGPCRs. Two models account for the elusive link between these critical features. Mechanical challenge to the receptor causes: (1) physical disruption of the heterodimer at the GPS thereby exposing the tethered agonist. In this scenario, GPS cleavage is absolutely essential for receptor activity; (2) Allosteric changes of the GAIN domain, e.g., through isomerization of the tethered agonist-7TM region, that allow for the engagement of the Stachel with the 7TM. In this situation, GPS cleavage and disruption of the NTF-CTF receptor heterodimer are not necessary for receptor activity. This study found that autoproteolytic cleavage is not required for the perception and transduction of vibrational mechanical stimuli by dCIRL (Scholz, 2017).

This study further uncovered that the concomitant disruption of Stachel and autoproteolysis disables dCIRL's mechanosensory function in ChO neurons. Thus, the tethered agonist concept pertains to aGPCRs in Drosophila. Notably, these findings also demonstrate that classical GPS mutations have similar biochemical but different physiological effects in vivo (Scholz, 2017).

Finally, this study interrogated intracellular signaling by dCIRL. In contrast to previously described Gαs coupling of rat and nematode latrophilins (Müller, 2015), the mechanosensory response of ChO neurons was decreased by optogenetic augmentation of adenylyl cylcase activity, and the mechanosensory deficit of dCirl^KO mutants was rescued by pharmacological inhibition of adenylyl cyclase. FRET measurements also directly demonstrated that mechanical stimulation reduces the cAMP concentration in the sensory neurons, and that this mechano-metabotropic coupling depends on dCIRL. Thus, dCIRL converts a mechanosensory signal into a drop of cAMP levels. This suggests that the Drosophila latrophilin entertains a cascade that inhibits adenylyl cyclases or stimulates phosphodiesterases in ChO neurons, and that G-protein coupling pathways by latrophilin homologs may depend on species and/or cell type (Scholz, 2017).

Members of the aGPCR family are associated with a vast range of physiological processes extending beyond canonical neuronal mechanosensation. For example, dysfunction of ADGRG1/GPR56 causes polymicrogyria, ADGRF5/GPR116 controls pulmonary surfactant production, genetic lesions in many aGPCR loci are associated with a roster of cancer types and ADGRE2/EMR2 regulates mast cell degranulation. Intriguingly, a point mutation in the GAIN domain of ADGRE2 sensitizes the receptor to mechanical stimuli in kindreds of patients suffering from vibratory urticaria. The results now provide a basis to test the generality of the concept that aGPCRs are metabotropic mechanosensors also outside classical mechanosensory structures, and aid in understanding the contribution of ailing aGPCR signaling in diseased tissues (Scholz, 2017).

Antinociceptive modulation by the adhesion GPCR CIRL promotes mechanosensory signal discrimination

Adhesion-type GPCRs (aGPCRs) participate in a vast range of physiological processes. Their frequent association with mechanosensitive functions suggests that processing of mechanical stimuli may be a common feature of this receptor family. Previous studies reported that the Drosophila aGPCR CIRL sensitizes sensory responses to gentle touch and sound by amplifying signal transduction in low-threshold mechanoreceptors. This study shows that Cirl is also expressed in high-threshold mechanical nociceptors where it adjusts nocifensive behaviour under physiological and pathological conditions. Optogenetic in vivo experiments indicate that CIRL lowers cAMP levels in both mechanosensory submodalities. However, contrasting its role in touch-sensitive neurons, CIRL dampens the response of nociceptors to mechanical stimulation. Consistent with this finding, rat nociceptors display decreased Cirl1 expression during allodynia. Thus, cAMP-downregulation by CIRL exerts opposing effects on low-threshold mechanosensors and high-threshold nociceptors. This intriguing bipolar action facilitates the separation of mechanosensory signals carrying different physiological information (Dannhauser, 2020).

Mechanical forces are detected and processed by the somatosensory system. Mechanosensation encompasses the distinct submodalities of touch, proprioception, and mechanical nociception. Touch plays an important discriminative role and contributes to social interactions. Nociception reports incipient or potential tissue damage. It triggers protective behaviours and can give rise to pain sensations. Thus, physically similar signals can carry fundamentally different physiological information, depending on stimulus intensity. Whereas innocuous touch sensations rely on low-threshold mechanosensory neurons, noxious mechanical stimuli activate high-threshold mechanosensory neurons, i.e. nociceptors. While mechanisms to differentiate these mechanosensory submodalities are essential for survival, little is known how this is achieved at cellular and molecular levels (Dannhauser, 2020).

The activity of nociceptors can be increased through sensitization, e.g. upon inflammation, and decreased through antinociceptive processes, leading to pain relief. In both cases, G protein-coupled receptors (GPCRs) play an important modulatory role. Receptors that couple to heterotrimeric Gq/11 or Gs proteins, like the prostaglandin EP2 receptor, increase the excitability of nociceptors by activating phospholipase C and adenylyl cyclase pathways, respectively. In contrast, Gi/o-coupled receptors, which are gated by soluble ligands like morphine and endogenous opioid neuropeptides generally inhibit nociceptor signalling. In mammalian nociceptors, cell surface receptors that couple to Gi/o proteins are located at presynaptic sites in the dorsal horn of the spinal cord, where they reduce glutamate release, at somata in dorsal root ganglia (DRG), and at peripheral processes, where they suppress receptor potential generation (Dannhauser, 2020).

Research on mechanosensation has focussed mainly on receptors that transduce mechanical force into electrical current, and the function of such mechanosensing ion channels is currently the subject of detailed investigations. In contrast, evidence for mechano-metabotropic signal transfer and compelling models of force conversion into an intracellular second messenger response are limited, despite the vital role of metabotropic modulation in all corners of physiology. Adhesion-type GPCRs (aGPCRs), a large molecule family with over 30 members in humans, operate in diverse physiological settings. Correspondingly, these receptors are associated with diverse human diseases, such as developmental disorders, defects of the nervous system, allergies and cancer. In contrast to most members of the GPCR phylum, aGPCRs are not activated by soluble ligands. Instead, aGPCRs interact with partner molecules tethered to membranes or fixed to the extracellular matrix via their long, adhesive N-terminal domain. This arrangement positions aGPCRs as metabotropic mechanosensors, which translate a relative displacement of the receptor-bearing cell into an intracellular second messenger signal (Dannhauser, 2020).

CIRL (ADGRL/Latrophilin, Lphn), one of the oldest members of the aGPCR family, is expressed in the neuronal dendrites and cilia of Drosophila larval chordotonal organs (ChOs), mechanosensory structures that respond to gentle touch, sound, and proprioceptive input. Here, mechanical stimulation of CIRL triggers a conformational change of the protein and activation via its tethered agonist (Stachel). Signalling by the activated receptor reduces intracellular cAMP levels, which in turn sensitizes ChO neurons and potentiates the mechanically-evoked receptor potential (Scholz, 2017). The current study shows that CIRL also adjusts the activity of nociceptors, which respond to strong mechanical stimuli. Here, too, its function is consistent with Gi/o coupling. However, in contrast to touch-sensitive ChO neurons, nociceptors are sensitized by elevated cAMP concentrations and toned down by an antinociceptive and Stachel-independent action of CIRL. As a result of curtailing cAMP production, CIRL modulates neural processing of noxious harsh and innocuous gentle touch bidirectionally. This elegant signalling logic serves signal discrimination by helping to separate mechanosensory submodalities (Dannhauser, 2020).

This study provides evidence that CIRL, an evolutionarily conserved aGPCR, reduces nociceptor responses to mechanical insult in Drosophila larvae. This modulation operates in the opposite direction to the sensitization of touch sensitive neurons by CIRL. In both types of mechanosensors, these effects are connected to CIRL-dependent decreases of cAMP levels. The opposing cell physiological outcomes, in turn, likely arise from specific adjustments of different effector proteins through cAMP-signalling. Candidate effectors are mechanotransduction channels and ion channels, which are mechanically-insensitive but influence the rheobase, i.e. the threshold current of the sensory neuron (Dannhauser, 2020).

The transient receptor potential (TRP) channel subunits NOMPC (no receptor potential, TRPN), NAN (nanchung, TRPV), and IAV (inactive, TRPV) govern mechanosensation by larval ChO neurons. The mechanically gated ion channel Piezo, the DEG/ENaC subunit Pickpocket, and the TRPN channel Painless, on the other hand, are required for mechanical nociception in Drosophila. It is therefore conceivable that the receptor potential generated by these different mechanotransducers may be modulated in opposite directions, i.e., decreased in ChO neurons and increased in nociceptors, by cAMP/PKA (protein kinase A)-dependent channel phosphorylation. Matching the results in Drosophila, enhanced nociceptor activity in mammals has been linked to elevated cAMP levels. For example, mechanical hyperalgesia during inflammation involves cAMP-modulated HCN channels and sensitization of mammalian Piezo2 via PKA and protein kinase C (PKC)-based signalling. Conversely, Gi/o-coupled receptors, such as opioid, somatostatin, and GABAB receptors, counteract cAMP-dependent nociceptor sensitization. In addition to this second messenger pathway, Gβγ subunits of Gi/o-coupled GPCRs can directly interact with ion channels. Thereby nociceptor signalling can be suppressed via activation of G protein regulated inwardly rectifying K+ channels (GIRK) or by inhibition of voltage-gated Ca2+ channels. Recent work has identified that CIRL2 and CIRL3 promote synapse formation in the mouse hippocampus (Sando, 2019). While Drosophila CIRL may also shape synaptic connectivity, the current results indicate that CIRL modulates the mechanically-evoked activity of nociceptors independently of such an additional function (Dannhauser, 2020).

The present findings show that CIRL decreases the activity of C4da neurons independently of mechanotransduction and that the aGPCR feeds into the same pathway as the adenylyl cyclase. Taken together, this strongly suggests that Gi/o coupling by CIRL regulates cAMP-dependent modulation of ion channels, which control nociceptor excitability. Work in cell culture has put forward a model in which Stachel-dependent and -independent aGPCR activation triggers different downstream signalling pathways. The current study provides evidence in support of such a dual activation model in a physiological setting. The dispensability of an intact Stachel sequence in mechanical nociceptors and its necessity in touch-sensitive neurons argues for alternative activation modes of CIRL in these two types of mechanosensory neurons. This raises the intriguing possibility that such functional differentiation may be connected to specific downstream effects, e.g. Stachel-dependent, phasic modulation of mechanotransduction in ChO neurons versus Stachel-independent, tonic modulation of nociceptor excitability (Dannhauser, 2020).

Many genes display altered expression in DRG neurons in neuropathy. For example, receptors and ion channels involved in sensitization are upregulated, whereas endogenous antinociceptive mechanisms, including opioid receptors and their peptides, are downregulated in certain neuropathy models. Thus, neuropathy not only enhances pro-nociceptive mechanisms but also decreases endogenous antinociceptive pathways. This analysis of rodent DRGs indicates that neuropathy-induced allodynia correlates with reduced Cirl1 expression in IB4-positive non-peptidergic nociceptors, a class of neurons, which have been linked to mechanical inflammatory hypersensitivity. It is therefore tempting to speculate that CIRL operates via a conserved antinociceptive mechanism in both invertebrate and mammalian nociceptors to reduce cAMP concentrations. Future work will have to test this hypothesis by examining a direct causal relation between CIRL activation and nociceptor attenuation in the mammalian peripheral nervous system and to explore whether metabotropic mechanosensing by CIRL is a possible target for analgesic therapy. Limited options for treating chronic pain have contributed to the current opioid epidemic. Opioids are powerful analgesics but have severe side effects and lead to addiction mainly through activation of receptors in the central nervous system. There is thus a strong incentive to develop novel peripherally acting pain therapeutics (Dannhauser, 2020).

The specificity theory, put forward by Sherrington more than 100 years ago, defines nociceptors as a functionally distinct subtype of nerve endings, which are specifically tuned to detect harmful, high-intensity stimuli. The results reported in the present study are consistent with this validated concept and identify a physiological mechanism, which contributes to the functional specialization. On the one hand, CIRL helps set the high activation threshold of mechanical nociceptors, while on the other hand, CIRL lowers the activation threshold of touch sensitive neurons. This bidirectional adjustment, attributable to cell-specific effects of cAMP, moves both submodalities further apart and sharpens the contrast of mechanosensory signals carrying different information (Dannhauser, 2020).

Oriented cell division in the C. elegans embryo is coordinated by G-protein signaling dependent on the adhesion GPCR LAT-1

Orientation of spindles and cell division planes during development of many species ensures that correct cell-cell contacts are established, which is vital for proper tissue formation. This is a tightly regulated process involving a complex interplay of various signals. The molecular mechanisms underlying several of these pathways are still incompletely understood. This study identified the signaling cascade of the C. elegans latrophilin homolog LAT-1, an essential player in the coordination of anterior-posterior spindle orientation during the fourth round of embryonic cell division. The receptor mediates a G protein-signaling pathway revealing that G-protein signaling in oriented cell division is not solely GPCR-independent. Genetic analyses showed that through the interaction with a Gs protein LAT-1 elevates intracellular cyclic AMP (cAMP) levels in the C. elegans embryo. Stimulation of this G-protein cascade in lat-1 null mutant nematodes is sufficient to orient spindles and cell division planes in the embryo in the correct direction. Finally, LAT-1 was shown to be activated by an intramolecular agonist to trigger this cascade. These data support a model in which a novel, GPCR-dependent G protein-signaling cascade mediated by LAT-1 controls alignment of cell division planes in an anterior-posterior direction via a metabotropic Gs-protein/adenylyl cyclase pathway by regulating intracellular cAMP levels (Muller, 2015).

Latrophilins function as heterophilic cell-adhesion molecules by binding to teneurins: regulation by alternative splicing

Latrophilin-1, -2, and -3 are adhesion-type G protein-coupled receptors that are auxiliary alpha-latrotoxin receptors, suggesting that they may have a synaptic function. Using pulldowns, this study identified teneurins (see Tenascin major and Tenascin accessory), type II transmembrane proteins that are also candidate synaptic cell-adhesion molecules, as interactors for the lectin-like domain of latrophilins. Teneurin are shown to bind to latrophilins with nanomolar affinity, and this binding mediates cell adhesion, consistent with a role of teneurin binding to latrophilins in trans-synaptic interactions. All latrophilins are subject to alternative splicing at an N-terminal site; in latrophilin-1, this alternative splicing modulates teneurin binding but has no effect on binding of latrophilin-1 to another ligand, FLRT3. Addition to cultured neurons of soluble teneurin-binding fragments of latrophilin-1 decreased synapse density, suggesting that latrophilin binding to teneurin may directly or indirectly influence synapse formation and/or maintenance. These observations are potentially intriguing in view of the proposed role for Drosophila teneurins in determining synapse specificity. However, teneurins in Drosophila were suggested to act as homophilic cell-adhesion molecules, whereas the current findings suggest a heterophilic interaction mechanism. Thus, whether mammalian teneurins also are homophilic cell-adhesion molecules was tested, in addition to binding to latrophilins as heterophilic cell-adhesion molecules. Strikingly, it was found that although teneurins bind to each other in solution, homophilic teneurin-teneurin binding is unable to support stable cell adhesion, different from heterophilic teneurin-latrophilin binding. Thus, mammalian teneurins act as heterophilic cell-adhesion molecules that may be involved in trans-neuronal interaction processes such as synapse formation or maintenance (Boucard, 2014).

Latrophilin 1 and its endogenous ligand Lasso/teneurin-2 form a high-affinity transsynaptic receptor pair with signaling capabilities

Latrophilin 1 (LPH1), a neuronal receptor of alpha-latrotoxin, is implicated in neurotransmitter release and control of presynaptic Ca(2+). As an 'adhesion G-protein-coupled receptor,' LPH1 can convert cell surface interactions into intracellular signaling. To examine the physiological functions of LPH1, wLPH1's extracellular domain was used to purify its endogenous ligand. A single protein of approximately 275 kDa was isolated from rat brain and termed Lasso. Peptide sequencing and molecular cloning have shown that Lasso is a splice variant of teneurin-2, a brain-specific orphan cell surface receptor with a function in neuronal pathfinding and synaptogenesis. This study shows that LPH1 and Lasso interact strongly and specifically. They are always copurified from rat brain extracts. Coculturing cells expressing LPH1 with cells expressing Lasso leads to their mutual attraction and formation of multiple junctions to which both proteins are recruited. Cells expressing LPH1 form chimerical synapses with hippocampal neurons in cocultures; LPH1 and postsynaptic neuronal protein PSD-95 accumulate on opposite sides of these structures. Immunoblotting and immunoelectron microscopy of purified synapses and immunostaining of cultured hippocampal neurons show that LPH1 and Lasso are enriched in synapses; in both systems, LPH1 is presynaptic, whereas Lasso is postsynaptic. A C-terminal fragment of Lasso interacts with LPH1 and induces Ca(2+) signals in presynaptic boutons of hippocampal neurons and in neuroblastoma cells expressing LPH1. Thus, LPH1 and Lasso can form transsynaptic complexes capable of inducing presynaptic Ca(2+) signals, which might affect synaptic functions (Silva, 2011).

LPH1 has been implicated in multiple phenomena, including binding of α-LTX, release of neurotransmitters, intracellular signaling, neuronal morphogenesis, and mental conditions. However, further studies of LPH1 require the identification of its endogenous ligand. Using LPH1-affinity chromatography, this study has now isolated such a ligand. Lasso is a splice variant of teneurin-2. It interacts with LPH1 specifically and strongly, but binds very weakly to LPH2 and does not bind to LPH3. Reciprocally, sequencing results and LPH1 binding suggest that LPH1 interacts with Lasso/teneurin-2 only, and not with teneurin-1, -3, or -4 (Silva, 2011).

Both LPH1 and Lasso/teneurin-2 are highly abundant in the brain. Can they mediate neuronal cell interaction? Teneurin is proteolyzed between the TMR and EGF repeats (see Kenzelmann, 2008), and this could preclude its receptor activity. However, only a proportion of teneurin is cleaved, resulting in two bands on reducing SDS gels. The fragment remains anchored on the cell surface, probably as part of the homodimer. This makes Lasso a bona fide cell-surface receptor (Silva, 2011).

Accordingly, Lasso and LPH1 mediate heterophilic cell-cell contacts between expressing cells in cocultures and formation of artificial synapses between fibroblasts and neurons. Moreover, the data indicate that in cultured neurons and mature brain, LPH1 is localized in the presynaptic membranes, whereas Lasso is mostly postsynaptic. Given the size of LPH1 (14 nm) and Lasso (~30 nm), their complex can span the synaptic cleft (20-30 nm), allowing this receptor pair to connect neurons at synapses (Silva, 2011).

The LPH1-Lasso interaction is not purely structural. LPH1 mediates signaling induced by LTX^N4C both in model cells expressing exogenous LPH1 and in organotypic hippocampal cultures. This signaling requires the CTF and involves the activation of phospholipase C, production of inositol-trisphosphate, and release of stored Ca²⁺. This study demonstrates that a soluble C-terminal fragment of Lasso also induces an increase in cytosolic Ca²⁺ in NB2a cells expressing LPH1 and in hippocampal neurons. Such a rise in cytosolic Ca²⁺ in neurons could modulate neurotransmitter release (Silva, 2011).

Interestingly, teneurin contains a sequence termed teneurin C-terminal-associated peptide (TCAP) that resembles corticotropin-releasing factor. It is hypothesized that TCAP is cleaved from teneurin and acts as a soluble ligand of unknown receptors (Wang, 2005). Synthetic TCAP regulates cAMP in immortalized neurons and, when injected cerebrally, affects behaviors related to stress and anxiety. However, there is no evidence that TCAP is released in vivo. The current work suggests an alternative possibility: TCAP, being part of Lasso, affects animal behavior by stimulating LPH1. This is supported by LPH being implicated in schizophrenia, anxiety (offspring killing by LPH1^−/− mice), and attention deficit/hyperactivity disorder (Silva, 2011).

The current findings raise several interesting questions. Does Lasso send an intracellular signal in response to LPH1 binding? What are the relationships among the four teneurin homologs and the three LPH proteins found in most vertebrates? Can the LPH1–Lasso interaction affect synaptogenesis, neurotransmitter release, or synaptic plasticity? Answering these questions will provide important insights into the physiological functions of these two families of neuronal cell surface receptors (Silva, 2011).

ADHD-associated dopamine transporter, latrophilin and neurofibromin share a dopamine-related locomotor signature in Drosophila

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder with hyperactivity as one of the hallmarks. Aberrant dopamine signaling is thought to be a major theme in ADHD, but how this relates to the vast majority of ADHD candidate genes is illusive. This study reports a Drosophila dopamine-related locomotor endophenotype that is shared by pan-neuronal knockdown of orthologs of the ADHD-associated genes Dopamine transporter (DAT1) and Latrophilin (LPHN3), and of a gene causing a monogenic disorder with frequent ADHD comorbidity: Neurofibromin (NF1). The locomotor signature was not found in control models and could be ameliorated by methylphenidate, validating its relevance to symptoms of the disorder. The Drosophila ADHD endophenotype can be further exploited in high throughput to characterize the growing number of candidate genes. It represents an equally useful outcome measure for testing chemical compounds to define novel treatment options (van der Voet, 2015).

Whereas in zebrafish it was found that latrophilin knockdown mutants show severe disorganization of the dopaminergic system (Lange, 2012), its development was left intact in the Drosophila knockdown model. This allowed gene function to be addressed independent of compromised circuits. In the Drosophila brain, loss of DAT, latrophilin, and Nf1 caused hyperactivity and reduced sleep in a light-dependent manner, phenocopying acute activation of dopaminergic neurons. That MPH, a drug that prolongs residence of secreted dopamine in the synaptic cleft and is thought to increase dopamine signaling, can improve ADHD-like phenotypes seems paradoxical but is a known phenomenon. It was found that expression of DAT carrying a mutation found in ADHD causes anomalous dopamine efflux, leading to elevated synaptic dopamine levels that could be rescued with MPH. Locomotor hyperactive mice lacking DAT (DAT-KO) show a marked reduction of locomotor activity in response to MPH administration, demonstrating the method of action is more complex than just DAT antagonism. This can include cross-talk between the D2 dopamine receptor (D2R), the rate-limiting enzyme for the biosynthesis of dopamine (TH) and the dopamine transporter (DAT). In Drosophila, MPH rescued defective optomotor response caused by activated but not by inhibited dopaminergic neurons. Further research is needed to understand the mechanisms linking LPHN3 and NF1 with dopamine signaling (van der Voet, 2015).

Latrophilin GPCRs direct synapse specificity by coincident binding of FLRTs and teneurins

Bidirectional signaling by cell adhesion molecules is thought to mediate synapse formation, but the mechanisms involved remain elusive. This study found that the adhesion G protein-coupled receptors latrophilin-2 and latrophilin-3 selectively direct formation of perforant-path and Schaffer-collateral synapses, respectively, to hippocampal CA1-region neurons. Latrophilin-3 binds to two transcellular ligands: fibronectin leucine-rich repeat transmembrane proteins (FLRTs) and teneurins. In transgenic mice in vivo, both binding activities were required for input-specific synapse formation, which suggests that coincident binding of both ligands is necessary for synapse formation. In cultured neurons in vitro, teneurin or FLRT alone did not induce excitatory synapse formation, whereas together they potently did so. Thus, postsynaptic latrophilins promote excitatory synapse formation by simultaneous binding of two unrelated presynaptic ligands, which is required for formation of synaptic inputs at specific dendritic localizations (Sando, 2019).

How synapses form, how they are maintained, and what molecular processes establish specificity in synaptic connections remain fundamental unanswered questions in neuroscience. This study provides three findings that reveal mechanisms involved in input-specific synapse formation in the brain and suggest an explanation for synapse specificity (Sando, 2019).

First, this study has shown that Lphn3 is specifically targeted to the dendritic domains of the S. oriens and S. radiatum of hippocampal CA1 pyramidal neurons, whereas the highly homologous Lphn2 is specifically targeted to the S. lacunosum-moleculare in the same neurons. Both Lphn2 and Lphn3 are essential for subsets of excitatory synapses on the dendritic domain to which they are targeted, suggesting that different isoforms of the same postsynaptic protein family differentially function in distinct synapses. These findings thus provide an explanation for the evolution of homologous adhesion GPCRs and their coexpression in the same neuron, and reveal that different isoforms of a postsynaptic cell recognition molecule can be targeted to distinct dendritic domains (Sando, 2019).

Second, this study has shown that autoproteolysis mediated by the GAIN domain-a canonical feature of adhesion GPCRs-is not required for Lphn3 function, suggesting that their activation does not involve the exposure of an intrinsic tethered agonist that is rendered competent for receptor binding by removal of the extracellular domains of Lphn3 (Sando, 2019).

Third, this study has shown that individual inactivation of FLRT binding or of teneurin binding to Lphn3 blocked its function in synapse formation, and that in the in vitro synapse formation paradigm, teneurin-2 and FLRT3 induced excitatory synapse formation only when they were coexpressed. Even when FLRT3 and teneurin-2 were coexpressed, only the teneurin-2 splice variant capable of binding to latrophilins was active in synapse formation. These results suggest that the requirement for two simultaneous ligands enables a higher specificity in synapse formation. More generally, the coincidence signaling by multiple ligands as described in this study contributes to the emerging realization that signal integration and coincidence detection are a key feature in synaptic plasticity and neural circuit. The results suggest that input-specific synapse formation requires integration of multiple transsynaptic signals acting on latrophilin adhesion GPCRs (Sando, 2019).

These results are at odds with several previous results. It has been proposed that latrophilins are presynaptic and FLRTs are postsynaptic, but this conclusion was largely based on the notion that latrophilins as α-latrotoxin receptors should be presynaptic. Moreover, a recent study arguing for a postsynaptic localization of FLRT2 is confounded by the use of an antibody targeting the FLRT2 extracellular region for localization analysis, which is presumably localized in the synaptic cleft, and the use of short hairpin RNA-mediated knockdowns, which are difficult to control. It was also proposed that teneurins act in establishing synaptic connectivity not as heterophilic but as homophilic cell adhesion molecules, but in assays described in this paper, teneurins do not engage as homophilic cell adhesion molecules, and teneurins act exclusively as presynaptic cell adhesion molecules (Sando, 2019).

The results raise multiple questions. For example, what is the nature of the postsynaptic signal that is activated by latrophilins during synapse formation? How is the specificity of Lphn2 and Lphn3 for different dendritic domains in the same pyramidal neuron determined, and is this due to intrinsic sequence determinants or to differential ligand-binding affinities? What postsynaptic ligands mediate teneurin action in inhibitory synapse formation? FLRT3 can simultaneously bind to Lphn3 and to Unc5 (a Netrin receptor protein involved in axon guidance during development) in a trans configuration, which suggests that the transsynaptic teneurin-latrophilin-FLRT complex may be even larger. As a result, this complex may include postsynaptic Unc5, which in turn could bind to yet another presynaptic adhesion molecule. These large, multiprotein transsynaptic complexes may be modular and may differ in distinct synapse subtypes to increase specificity and generate functional diversity. Thus, the overall portrait of synapse formation emerging from these data is that different latrophilin isoforms are targeted to defined postsynaptic dendritic domains, where they mediate specific excitatory synapse formation by binding to presynaptic FLRTs and teneurins on incoming axons (Sando, 2019).

Alternative splicing controls teneurin-latrophilin interaction and synapse specificity by a shape-shifting mechanism

The trans-synaptic interaction of the cell-adhesion molecules teneurins (TENs; see Drosophila Ten-m) with latrophilins (LPHNs/ADGRLs; see Drosophila Cirl) promotes excitatory synapse formation when LPHNs simultaneously interact with FLRTs. Insertion of a short alternatively-spliced region within TENs abolishes the TEN-LPHN interaction and switches TEN function to specify inhibitory synapses. How alternative-splicing regulates TEN-LPHN interaction remains unclear. This study reports the 2.9 Å resolution cryo-EM structure of the TEN2-LPHN3 complex and describes the trimeric TEN2-LPHN3-FLRT3 complex. The structure reveals that the N-terminal lectin domain of LPHN3 binds to the TEN2 barrel at a site far away from the alternatively spliced region. Alternative-splicing regulates the TEN2-LPHN3 interaction by hindering access to the LPHN-binding surface rather than altering it. Strikingly, mutagenesis of the LPHN-binding surface of TEN2 abolishes the LPHN3 interaction and impairs excitatory but not inhibitory synapse formation. These results suggest that a multi-level coincident binding mechanism mediated by a cryptic adhesion complex between TENs and LPHNs regulates synapse specificity (Li, 2020).

Catching Latrophilin With Lasso: A Universal Mechanism for Axonal Attraction and Synapse Formation

Latrophilin-1 (LPHN1; see Drosophila Cirl) was isolated as the main high-affinity receptor for alpha-latrotoxin from black widow spider venom, a powerful presynaptic secretagogue. As an adhesion G-protein-coupled receptor, LPHN1 is cleaved into two fragments, which can behave independently on the cell surface, but re-associate upon binding the toxin. This triggers intracellular signaling that involves the Galphaq/phospholipase C/inositol 1,4,5-trisphosphate cascade and an increase in cytosolic Ca(2+), leading to vesicular exocytosis. This study isolated its endogenous ligand, teneurin-2/Lasso (see Drosophila Ten-m). Both LPHN1 and Ten2/Lasso are expressed early in development and are enriched in neurons. LPHN1 primarily resides in axons, growth cones and presynaptic terminals, while Lasso largely localizes on dendrites. LPHN1 and Ten2/Lasso form a trans-synaptic receptor pair that has both structural and signaling functions. However, Lasso is proteolytically cleaved at multiple sites and its extracellular domain is partially released into the intercellular space, especially during neuronal development, suggesting that soluble Lasso has additional functions. This study discovered that the soluble fragment of Lasso can diffuse away and bind to LPHN1 on axonal growth cones, triggering its redistribution on the cell surface and intracellular signaling which leads to local exocytosis. This causes axons to turn in the direction of spatio-temporal Lasso gradients, while LPHN1 knockout blocks this effect. These results suggest that the LPHN1-Ten2/Lasso pair can participate in long- and short-distance axonal guidance and synapse formation (Ushkaryov, 2019).

Structural Basis of Teneurin-Latrophilin Interaction in Repulsive Guidance of Migrating Neurons

Teneurins are ancient metazoan cell adhesion receptors that control brain development and neuronal wiring in higher animals. The extracellular C terminus binds the adhesion GPCR Latrophilin, forming a trans-cellular complex with synaptogenic functions. However, Teneurins (see Drosophila Ten-m), Latrophilins (see Drosophila Cirl), and FLRT proteins are also expressed during murine cortical cell migration at earlier developmental stages. This study presents crystal structures of Teneurin-Latrophilin complexes that reveal how the lectin and olfactomedin domains of Latrophilin bind across a spiraling beta-barrel domain of Teneurin, the YD shell. Structure-based protein engineering was coupled to biophysical analysis, cell migration assays, and in utero electroporation experiments to probe the importance of the interaction in cortical neuron migration. Binding of Latrophilins to Teneurins and FLRTs directs the migration of neurons using a contact repulsion-dependent mechanism. The effect is observed with cell bodies and small neurites rather than their processes. The results exemplify how a structure-encoded synaptogenic protein complex is also used for repulsive cell guidance (Del Toro, 2020).

Search PubMed for articles about Drosophila Latrotoxin receptor

Arac, D., Boucard, A. A., Bolliger, M. F., Nguyen, J., Soltis, S. M., Sudhof, T. C. and Brunger, A. T. (2012). A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. EMBO J 31: 1364-1378. PubMed ID: 22333914

Boucard, A. A., Maxeiner, S. and Sudhof, T. C. (2014). Latrophilins function as heterophilic cell-adhesion molecules by binding to teneurins: regulation by alternative splicing. J Biol Chem 289: 387-402. PubMed ID: 24273166

Dannhauser, S., Lux, T. J., Hu, C., Selcho, M., Chen, J. T., Ehmann, N., Sachidanandan, D., Stopp, S., Pauls, D., Pawlak, M., Langenhan, T., Soba, P., Rittner, H. L. and Kittel, R. J. (2020). Antinociceptive modulation by the adhesion GPCR CIRL promotes mechanosensory signal discrimination. Elife 9. PubMed ID: 32996461

Del Toro, D., Carrasquero-Ordaz, M. A., Chu, A., Ruff, T., Shahin, M., Jackson, V. A., Chavent, M., Berbeira-Santana, M., Seyit-Bremer, G., Brignani, S., Kaufmann, R., Lowe, E., Klein, R. and Seiradake, E. (2020). Structural Basis of Teneurin-Latrophilin Interaction in Repulsive Guidance of Migrating Neurons. Cell 180(2): 323-339 e319. PubMed ID: 31928845

Fredriksson, R. and Schioth, H. B. (2005). The repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol Pharmacol 67: 1414-1425. PubMed ID: 15687224

Kenzelmann, D., Chiquet-Ehrismann, R., Leachman, N. T. and Tucker, R. P. (2008). Teneurin-1 is expressed in interconnected regions of the developing brain and is processed in vivo. BMC Dev Biol 8: 30. PubMed ID: 18366734

Langenhan, T., Promel, S., Mestek, L., Esmaeili, B., Waller-Evans, H., Hennig, C., Kohara, Y., Avery, L., Vakonakis, I., Schnabel, R. and Russ, A. P. (2009). Latrophilin signaling links anterior-posterior tissue polarity and oriented cell divisions in the C. elegans embryo. Dev Cell 17: 494-504. PubMed ID: 19853563

Lange, M., Norton, W., Coolen, M., Chaminade, M., Merker, S., Proft, F., Schmitt, A., Vernier, P., Lesch, K. P. and Bally-Cuif, L. (2012). The ADHD-linked gene Lphn3.1 controls locomotor activity and impulsivity in zebrafish. Mol Psychiatry 17: 855. PubMed ID: 22918194

Langenhan, T., Aust, G. and Hamann, J. (2013). Sticky signaling--adhesion class G protein-coupled receptors take the stage. Sci Signal 6: re3. PubMed ID: 23695165

Li, J., Xie, Y., Cornelius, S., Jiang, X., Sando, R., Kordon, S. P., Pan, M., Leon, K., Sudhof, T. C., Zhao, M. and Arac, D. (2020). Alternative splicing controls teneurin-latrophilin interaction and synapse specificity by a shape-shifting mechanism. Nat Commun 11(1): 2140. PubMed ID: 32358586

Liebscher, I., Schon, J., Petersen, S. C., Fischer, L., Auerbach, N., Demberg, L. M., Mogha, A., Coster, M., Simon, K. U., Rothemund, S., Monk, K. R. and Schoneberg, T. (2014). A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133. Cell Rep 9(6): 2018-2026. PubMed ID: 25533341

Monk, K. R., Hamann, J., Langenhan, T., Nijmeijer, S., Schoneberg, T. and Liebscher, I. (2015). Adhesion G Protein-Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms. Mol Pharmacol 88(3): 617-623. PubMed ID: 25956432

Muller, A., Winkler, J., Fiedler, F., Sastradihardja, T., Binder, C., Schnabel, R., Kungel, J., Rothemund, S., Hennig, C., Schoneberg, T. and Promel, S. (2015). Oriented Cell Division in the C. elegans Embryo Is Coordinated by G-Protein Signaling Dependent on the Adhesion GPCR LAT-1. PLoS Genet 11(10): e1005624. PubMed ID: 26505631

O'Sullivan, M. L., Martini, F., von Daake, S., Comoletti, D. and Ghosh, A. (2014). LPHN3, a presynaptic adhesion-GPCR implicated in ADHD, regulates the strength of neocortical layer 2/3 synaptic input to layer 5. Neural Dev 9: 7. PubMed ID: 24739570

Newton, F. G., zur Lage, P. I., Karak, S., Moore, D. J., Gopfert, M. C. and Jarman, A. P. (2012). Forkhead transcription factor Fd3F cooperates with Rfx to regulate a gene expression program for mechanosensory cilia specialization. Dev Cell 22: 1221-1233. PubMed ID: 22698283

Paavola, K. J., Sidik, H., Zuchero, J. B., Eckart, M. and Talbot, W. S. (2014). Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126. Sci Signal 7: ra76. PubMed ID: 25118328

Promel, S., Langenhan, T. and Arac, D. (2013). Matching structure with function: the GAIN domain of adhesion-GPCR and PKD1-like proteins. Trends Pharmacol Sci 34: 470-478. PubMed ID: 23850273

Retailleau, K. and Duprat, F. (2014). Polycystins and partners: proposed role in mechanosensitivity. J Physiol 592: 2453-2471. PubMed ID: 24687583

Sando, R., Jiang, X. and Sudhof, T. C. (2019). Latrophilin GPCRs direct synapse specificity by coincident binding of FLRTs and teneurins. Science 363(6429). PubMed ID: 30792275

Scholz, N., Gehring, J., Guan, C., Ljaschenko, D., Fischer, R., Lakshmanan, V., Kittel, R. J. and Langenhan, T. (2015). The adhesion GPCR Latrophilin/CIRL shapes mechanosensation. Cell Rep. PubMed ID: 25937282

Scholz, N., Guan, C., Nieberler, M., Grotemeyer, A., Maiellaro, I., Gao, S., Beck, S., Pawlak, M., Sauer, M., Asan, E., Rothemund, S., Winkler, J., Promel, S., Nagel, G., Langenhan, T. and Kittel, R. J. (2017). Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons. Elife 6. PubMed ID: 28784204

Silva, J. P., Lelianova, V. G., Ermolyuk, Y. S., Vysokov, N., Hitchen, P. G., Berninghausen, O., Rahman, M. A., Zangrandi, A., Fidalgo, S., Tonevitsky, A. G., Dell, A., Volynski, K. E. and Ushkaryov, Y. A. (2011). Latrophilin 1 and its endogenous ligand Lasso/teneurin-2 form a high-affinity transsynaptic receptor pair with signaling capabilities. Proc Natl Acad Sci U S A 108: 12113-12118. PubMed ID: 21724987

Stoveken, H. M., Hajduczok, A. G., Xu, L. and Tall, G. G. (2015). Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist. Proc Natl Acad Sci U S A 112(19): 6194-6199. PubMed ID: 25918380

Ushkaryov, Y. A., Lelianova, V. and Vysokov, N. V. (2019). Catching Latrophilin With Lasso: A Universal Mechanism for Axonal Attraction and Synapse Formation. Front Neurosci 13: 257. PubMed ID: 30967757

van der Voet, M., Harich, B., Franke, B. and Schenck, A. (2015). ADHD-associated dopamine transporter, latrophilin and neurofibromin share a dopamine-related locomotor signature in Drosophila. Mol Psychiatry [Epub ahead of print]. PubMed ID: 25962619

Wang, L., Rotzinger, S., Al Chawaf, A., Elias, C. F., Barsyte-Lovejoy, D., Qian, X., Wang, N. C., De Cristofaro, A., Belsham, D., Bittencourt, J. C., Vaccarino, F. and Lovejoy, D. A. (2005). Teneurin proteins possess a carboxy terminal sequence with neuromodulatory activity. Brain Res Mol Brain Res 133: 253-265. PubMed ID: 15710242

Yang, M. Y., Hilton, M. B., Seaman, S., Haines, D. C., Nagashima, K., Burks, C. M., Tessarollo, L., Ivanova, P. T., Brown, H. A., Umstead, T. M., Floros, J., Chroneos, Z. C. and St Croix, B. (2013). Essential regulation of lung surfactant homeostasis by the orphan G protein-coupled receptor GPR116. Cell Rep 3: 1457-1464. PubMed ID: 23684610

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Biological Overview

date revised: 20 September 2023

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