Environmental and social factors as determinants of respiratory dysfunction in junior schoolchildren in Moscow

BACKGROUND: The process of industrialization of the USSR has left a legacy of widespread and often poorly controlled pollution which is widely believed to have adverse implications for health, in particular for respiratory disease among children. OBJECTIVES: To assess the relationship between area of residence and respiratory function in junior schoolchildren in different districts of Moscow. METHODS: A survey was conducted of 539 children aged 6-12 years who attend school and live in one of three districts of Moscow with varying ambient pollution levels. Spirometry [forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)] was assessed at school by trained school health staff. Parents of the children completed a questionnaire asking about respiratory function and factors potentially associated with it, as well as about social and other factors that could influence respiratory development and the health status of their children. RESULTS: There was appreciable difference in the characteristics of the children from the three districts. Children from the lower pollutant districts were generally younger, had higher parental income, and were less frequently exposed to cigarette smoke at home. They were also less likely to report heavy lorry traffic in the streets outside their homes. After adjustment for age, gender and height the FVC was 7.6 per cent (3.6-11.5 per cent) lower in children from the medium pollution district and 9.9 per cent [95 per cent confidence interval (CI) 5.6-14.0 per cent] lower in children from the high pollution district compared with those in the least polluted district (p < 0.001 for trend). These differences were little affected by further adjustment for household income or exposure to household smoking. In contrast, FEV1 showed comparatively little variation across districts. The odds of a forced expiratory ratio (FER) <75 per cent were substantially lower in the high pollution compared with the low pollution district (odds ratio 0.10, 95per cent CI 0.03-0.32 after adjustment for age, gender and height), and there was clear evidence of a trend across pollution categories (p < 0.001). The frequency of reported allergy was also lower in the high pollution district. FVC increased, and the probability of a low FER decreased, with household income. CONCLUSION: Children from areas of high environmental pollution had lower lung capacity but also smaller risk of a low FER compared with those from cleaner areas. The extent to which these differences can be attributed to environmental pollution is unclear without more detailed study. However, socio-economic deprivation, which was associated with pollution, appears to be an important determinant of respiratory function although it was associated with a lower risk of an obstructive pattern of lung function tests.     

Evaluation of IDDM8 susceptibility locus in a Russian simplex family data set

Type 1 diabetes (T1D) susceptibility locus, IDDM8, has been accurately mapped to 200 kilobases at the terminal end of chromosome 6q27. This is within the region which harbours a cluster of three genes encoding proteasome subunit beta 1 (PMSB1), TATA-box binding protein (TBP) and a homologue of mouse programming cell death activator 2 (PDCD2). In this study, we evaluated whether these genes contribute to T1D susceptibility using the transmission disequilibrium test of the data set from 114 affected Russian simplex families. The A allele of the G/A1180 single nucleotide polymorphism (SNP) at the PDCD2 gene, which was significant in its preferential transfer from parents to diabetic children (75 transmissions vs. 47 non-transmissions, chi2=12.85, P corrected=0.0038), was found to be associated with T1D. G/A1180 dimorphism and two other SNPs, C/T771 TBP and G/T(-271) PDCD2, were shown to share three common haplotypes, two of which (A-T-G and A-T-T) have been associated with higher development risk of T1D. The third haplotype (G-T-G) was related to having a lower risk of disease. These findings suggest that the PDCD2 gene is a likely susceptibility gene for T1D within IDDM8. However, it was not possible to exclude the TBP gene from being another putative susceptibility gene in this region.     

Protein-protein interaction and functionTRPC channels

Since their identification in the concluding years of the last century, the mammalian transient receptor potential (canonical) (TRPC) channels have remained in the limelight as the primary candidates for the Ca²⁺ entry pathway activated by the hormones, growth factors, and neurotransmitters that exert their effect through activation of PLC. Although TRPC channels have been shown clearly to mediate, at least in part, receptor-activated Ca²⁺ entry in literally all cell types, several of their central characteristics, as recorded in expression systems using recombinant channels, differ from those of the native receptor-dependent Ca²⁺ influx channels. The present review attempts to highlight the interaction of TRPC channels with other proteins, which may explain the variability of TRPC channel activation and regulatory mechanisms observed with the native and recombinant channels. These include the homologous and heterotopous interactions of TRPC channel isoforms, the interaction of TRPC channels with calmodulin, PLC, IP₃ receptors, and with scaffolding proteins like InaD, EBP50/NEHRF, caveolin, Janctate and Homers.     

Control elements within the PWS/AS imprinting box and their function in the imprinting process

A cluster of imprinted genes on human chromosome 15q11-q13 (the PWS/AS domain) and its ortholog on mouse chromosome 7c is believed to be regulated by an imprinting control center. Although minideletions in this region in Angelman syndrome (AS) and Prader-Willi syndrome (PWS) patients revealed that two elements, shortest deletion regions of overlap in AS families and PWS families (AS-SRO and PWS-SRO), respectively, constitute the IC, the molecular mechanism that governs this regional control remains obscure. To understand how this imprinting center works, a mouse model was sought. The striking similarity between the human and mouse sequences allowed the generation of a minitransgene (AS-SMP) composed of AS-SRO and the Snrpn minimal promoter (SMP) the mouse ortholog of PWS-SRO. This minitransgene carries out, in a highly reliable and reproducible manner, all steps of the imprinting process. In an attempt to decipher the molecular mechanism of the imprinting process, we generated and tested for imprinting five minitransgenes based on AS-SMP, in which various parts of the 160 bp SMP were deleted. These experiments revealed a set of five cis elements that carry out the various steps of the imprinting process. This set includes: (i). two copies of a de novo methylation signal (DNS) that establish the maternal imprint during oogenesis; (ii). an allele discrimination signal that establishes the paternal imprint; and (iii). two elements that act together to maintain the paternal imprint. Two functionally redundant sets of the five elements were found on the respective endogenous mouse sequence explaining the previously published contradictory results of targeted deletion experiments. Together with the fact that all five elements bind specific proteins that are presumably the factors acting in trans in the imprinting process, our observations set the stage for a comprehensive study of the molecular mechanism involved in the control of the imprinting process.     

Silencing of SARS-CoV-2 with modified siRNA-peptide dendrimer formulation

Background

First vaccines for prevention of Coronavirus disease 2019 (COVID-19) are becoming available but there is a huge and unmet need for specific forms of treatment. In this study we aimed to evaluate the anti-SARS-CoV-2 effect of siRNA both in vitro and in vivo.

Methods

To identify the most effective molecule out of a panel of 15 in silico designed siRNAs, an in vitro screening system based on vectors expressing SARS-CoV-2 genes fused with the firefly luciferase reporter gene and SARS-CoV-2-infected cells was used. The most potent siRNA, siR-7, was modified by Locked nucleic acids (LNAs) to obtain siR-7-EM with increased stability and was formulated with the peptide dendrimer KK-46 for enhancing cellular uptake to allow topical application by inhalation of the final formulation – siR-7-EM/KK-46. Using the Syrian Hamster model for SARS-CoV-2 infection the antiviral capacity of siR-7-EM/KK-46 complex was evaluated.

Results

We identified the siRNA, siR-7, targeting SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) as the most efficient siRNA inhibiting viral replication in vitro. Moreover, we showed that LNA-modification and complexation with the designed peptide dendrimer enhanced the antiviral capacity of siR-7 in vitro. We demonstrated significant reduction of virus titer and lung inflammation in animals exposed to inhalation of siR-7-EM/KK-46 in vivo.

Conclusions

Thus, we developed a therapeutic strategy for COVID-19 based on inhalation of a modified siRNA-peptide dendrimer formulation. The developed medication is intended for inhalation treatment of COVID-19 patients.

     

Improved herbicide discovery using physico-chemical rules refined by antimalarial library screening

Herbicides have physico-chemical properties not unlike orally-delivered human drugs, but are known to diverge in their limits for proton donors, partition coefficients and molecular weight. To further refine rules specific for herbicides, we exploited the close evolutionary relationship between Plasmodium falciparum and plants by screening the entire Malaria Box, a chemical library of novel chemical scaffolds with activity against the blood stage of P. falciparum. Initial screening against Arabidopsis thaliana on agar media and subsequently on soil demonstrated the crucial nature of log P and formal charge are to active molecules. Using this information, a weighted scoring system was applied to a large chemical library of liver-stage effective antimalarial leads, and of the six top-scoring compounds, one had potency comparable to that of commercial herbicides. This novel compound, MMV1206386, has no close structural analogues among commercial herbicides. Physiological profiling suggested that MMV1206386 has a new mode of action and overall demonstrates how weighted rules can help during herbicide discovery programs.

Trawling hundreds of antimalarials for herbicides, we develop a weighted scoring system for the phys-chem ‘rules’ of herbicide-likeness. Using this, we discover the antimalarial MMV1206386 is herbicidal via a novel mode of action.     

Safety and Effectiveness of Essential Phospholipids Paste in Patients with Non-alcoholic Fatty Liver Disease or Viral Hepatitis

Background: Essential phospholipids (EPL) are used as adjuvant treatment in people with fatty liver disease and other chronic liver diseases. A new formulation of EPL paste was developed to improve patient compliance. The study was aimed to assess the safety, patient-reported outcomes, and impact on compliance of the new EPL paste formulation in patients with non-alcoholic fatty liver disease (NAFLD) or viral hepatitis.Methods: The study enrolled 147 patients (48.3% male; mean ± standard deviation (SD) age 44.8 ± 10.5 years) in the intention-to-treat population; 72.8% had NAFLD and 27.9% had viral hepatitis B (HBV) or hepatitis C (HCV). Patients received EPL paste (one 600 mg sachet 3 times daily) for 12 weeks, with 4-, 8-, and 12-week scheduled visits and a 13-week follow-up visit. Patient-reported outcomes were evaluated at 4, 8, and 12 weeks compared with baseline using dedicated Likert scales. Compliance was assessed by comparing actual versus prescribed dosing of the EPL.Results: After 12-week treatment with EPL paste, statistically significant improvements were observed in mean ± SD Global Overall Symptom scores (from 4.21 ± 1.09 to 1.87 ± 0.91; P < .01) and overall Gastrointestinal Symptom scores (from 19.91 ± 5.74 to 11.17 ± 3.57; P < .01), compared to baseline scores. Compliance with prescribed essential phospholipid treatment was 99% throughout the 12-week treatment period.Conclusion: Essential phospholipids paste had a favorable safety profile associated with improved gastrointestinal symptoms and with high levels of compliance in patients with NAFLD and viral hepatitis.     

One-pot synthesis of α-aminophosphonates by yttrium-catalyzed Birum–Oleksyszyn reaction

For the first time, yttrium triflate was used as an efficient green catalyst for the synthesis of α-aminophosphonates through a one-pot three-component Birum–Oleksyszyn reaction. Under the action of this Lewis acid, enhancement of the yield and reaction chemoselectivity was provided by the achievement of an appropriate balance in the complex network of reactions.

For the first time, yttrium triflate was used as an efficient green catalyst for the synthesis of α-aminophosphonates through a one-pot three-component Birum–Oleksyszyn reaction.

Multicomponent reactions are commonly used to achieve molecular complexity. In particular, one-pot three-component reactions have been exploited for the synthesis of α-aminophosphonates. These organophosphorus compounds have attracted the attention of medicinal chemists due to their similarity to α-amino acids. They find application in agriculture as plant growth regulators¹ and herbicides,² in medicinal chemistry as antibacterial,^3,4 antiviral⁵ and antitumor agents,⁶ activity-based probes,⁷ and building blocks for peptides and proteins.⁸ Since the first preparation of α-aminophosphonates, reported in 1952 by Fields,⁹ various methods for their synthesis have been proposed.^10–16 Nowadays, one-pot three-component condensation of aldehyde, amine, and phosphite, catalyzed by an excess of acetic acid, is the most common method due to its simplicity and, in general, high yields of products.⁴ Application of Lewis acids as the catalyst instead of Brønsted acids was first reported in 1973 by Birum.¹⁷ The advantage of Lewis acids is their compatibility with acid-sensitive functional groups that, under typical conditions (glacial acetic acid) would be degraded.Condensation of aldehyde, carbamate, and triaryl phosphite has been named as Birum–Oleksyszyn reaction.¹⁸ Recently, a new biologically active α-aminophosphonate (UAMC-00050) was developed at the University of Antwerp.^19–21 This diarylphosphonate shows good inhibitory activity against urokinase plasminogen activator (uPA), an enzyme involved in several physiological processes, such as tissue remodeling.²² uPA can be also involved in the development of different diseases, for example, thrombolytic disorder,²³ cancer,²⁴ and eye diseases.²⁵ UAMC-00050 is currently under investigation for the treatment of irritable bowel syndrome²⁶ and dry eye disease.²¹ The key step of the synthesis of UAMC-00050, proposed by Joossens et al.,^19,21 involves Birum–Oleksyszyn reaction, catalyzed by Cu(OTf)₂ in acetonitrile, which, on a small scale, provides 20% yield of the product (Scheme 1). In current work, a new catalyst has been introduced for the Birum–Oleksyszyn reaction. For the first time, we report the use of yttrium salt in a one-pot three-component synthesis of α-aminophosphonates, which provides a remarkable improvement of the yield of product for the key step in the synthesis of UAMC-00050. The scope of the protocol has been demonstrated on a variety of aldehydes, phosphites, and carbamates.Open in a separate windowScheme 1Conditions for the preparation of intermediate 4 in the synthesis of UAMC-00050 (5).In the frame of the dry eye disease drug development (IT-DED3) project,²⁷ we have worked toward upscaling of the synthetic route and providing larger amounts of UAMC-00050 for more detailed research of its biological activity.During our attempts to upscale the key step to 3.0 g scale, we noticed a considerable decrease of the yield of product from 20% to 11%. In our view, the poor outcome of the process cannot be attributed to the Birum–Oleksyszyn reaction alone. The nature of substituents in the target molecule affects the overall efficiency of the transformation through both the main and a number of side reactions (Scheme 2). This three-component reaction involves unstable paracetamol phosphite 1, aliphatic aldehyde 2 bearing Boc-protected amino group, and benzyl carbamate 3 (Scheme 1). In general, aliphatic aldehydes are less reactive in Birum–Oleksyszyn reaction, which consequently requires a stronger catalyst or longer reaction time to achieve satisfactory yield of product.^15,28 The imine generated from the condensation of carbamate and aldehyde is highly reactive and can add a second molecule of carbamate forming aminal 7.²⁹ Compound 7 can participate in Arbuzov-type reactions,³⁰ if, as hypothesized, it is converted into reactive cation 13 by Brønsted²⁹ or Lewis acid.³¹ However, Lewis acid-catalyzed reactions of aminal 7 or its analogs and triaryl phosphites are not known.Open in a separate windowScheme 2Birum–Oleksyszyn reaction as the key step and possible side reactions in the synthesis of UAMC-00050.The presence of paracetamol moiety complicates the synthesis due to the lower stability of its phosphorus esters both in starting triaryl phosphite and in the formed α-aminophosphonate. In the reaction environment, they readily hydrolyze with one equivalent of water formed in the condensation of aldehyde 2 and the carbamate 3 generating diarylphosphite 9 and monoaryl side product 10.As previously reported, product 4 is stable in the presence of water.²¹ However, under the reaction conditions, hydrolysis proceeds with the help of the Lewis acid.³² With prolonged reaction time (i.e., 24 h) we noticed a decrease in the yield of product 4 almost in half compared to the yield obtained in the reaction performed for 4 h and formation of acid 10 as the major side product.Application of N-Boc-protected starting material is also challenging, since, in the presence of a Lewis acid catalyst, partial removal of the Boc group takes place and unprotected amino aldehyde 11 forms black-brown polymer 12 (Scheme 2).Improving the overall efficiency of the synthesis of α-aminophosphonate 4 requires simultaneous promotion of imine formation and Birum–Oleksyszyn reaction and suppression of unwanted hydrolysis and Boc group removal. In search for optimal conditions, we initiated screening of various acidic catalysts using equimolar ratio (1 : 1 : 1) of aldehyde 2, carbamate 3, and phosphite 1 with 10 mol% load of the catalyst in MeCN performing the reaction at room temperature for 4 h.¹⁹ Acetonitrile proved to be an optimal solvent for the preparation of 4, it is polar enough to dissolve all the starting materials, it is not a concern for the environment, like DCM, and it does not hydrolyze the product like protic solvents: MeOH, EtOH and H₂O.In

Slow expanders invade by forming dented fronts in microbial colonies

Most organisms grow in space, whether they are viruses spreading within a host tissue or invasive species colonizing a new continent. Evolution typically selects for higher expansion rates during spatial growth, but it has been suggested that slower expanders can take over under certain conditions. Here, we report an experimental observation of such population dynamics. We demonstrate that mutants that grow slower in isolation nevertheless win in competition, not only when the two types are intermixed, but also when they are spatially segregated into sectors. The latter was thought to be impossible because previous studies focused exclusively on the global competitions mediated by expansion velocities, but overlooked the local competitions at sector boundaries. Local competition, however, can enhance the velocity of either type at the sector boundary and thus alter expansion dynamics. We developed a theory that accounts for both local and global competitions and describes all possible sector shapes. In particular, the theory predicted that a slower on its own, but more competitive, mutant forms a dented V-shaped sector as it takes over the expansion front. Such sectors were indeed observed experimentally, and their shapes matched quantitatively with the theory. In simulations, we further explored several mechanisms that could provide slow expanders with a local competitive advantage and showed that they are all well-described by our theory. Taken together, our results shed light on previously unexplored outcomes of spatial competition and establish a universal framework to understand evolutionary and ecological dynamics in expanding populations.

Population dynamics always unfold in a physical space. At small scales, microbes form tight associations with each other, substrates, or host cells (1, 2). At large scales, phytoplanktons and zooplanktons form complex patterns influenced by ecological interactions (3–5) and hydrodynamics (6, 7). Between these two extremes, populations constantly shrink and expand in response to changing conditions, and there is still a great deal to be learned about how spatial structure affects ecology and evolution (8–12). Better understanding of these eco-evolutionary dynamics is essential for management of invasive species (13, 14), controlling the growth of cancer (15), and preserving biodiversity (16, 17).It is particularly important to understand how natural selection operates at the edge of expanding populations. These expansion frontiers are hot spots of evolution because mutations that arise at the edge can rapidly establish over large areas via allele surfing or sectoring (18–21). Furthermore, numerous studies argue that selection at the expansion front favors faster expanders and therefore makes population control more difficult (22–32). Indeed, organisms that expand faster have a head start on growing into a new territory and may face weaker competition or better access to nutrients. A well-known example is the evolution of cane toads, which increased the expansion speed by fivefold over 50 y (33). Yet, despite substantial empirical evidence across many systems (23–26, 28–32), it has been suggested that the simple intuition of “faster runner wins the race” does not always hold.Two theoretical studies have found that slower dispersal could evolve in populations with a strong Allee effect, i.e., a negative growth rate at low population densities (34–36). Slow mutants nevertheless can take over the populations because they are less likely to disperse ahead of the front into regions with low densities and negative growth rates. In a different context, both theory and experiments have shown that slow cheaters could invade the growth front of fast cooperators (27, 37). In this system, the production of public goods allowed cooperators to expand faster, but made them vulnerable to the invasion by cheaters.The examples above show that slower expanders succeed in the presence of a tradeoff between local and global fitness. The global fitness is simply the expansion rate of a given species in isolation, which determines how quickly it can colonize an empty territory. When two species are well-separated in space, their competition is determined solely by the global fitness. In contrast, when the two species are present at the same location, their competition could involve differences in growth rates, production of public goods (38, 39), or secretion of toxins (40). We refer to such local competitive abilities as local fitness. It is natural to assume that slow expanders can win only if they are superior local competitors, but it is not clear a priori if this is actually feasible or how to integrate local and global fitness under various scenarios of spatial competition.Our interest in the interplay between local and global competition was sparked by an unusual spatial pattern in colonies of Raoultella planticola grown on agar plates. These colonies repeatedly developed depressions or dents along the edge. We found that dents were produced by a spontaneous mutant that expanded slower than the wild type, when in isolation. Thus, we discovered a convenient platform to explore the fate of slower expanders in spatial competition and to elucidate the tension between local and global fitness.In our experiment, the slower mutant took over the colony either while increasing in frequency homogeneously along the front or while forming pure, mutant-only sectors. When mutant sectors formed, they had an unusual “dented” or “V” shape. To explain this spatial pattern, we developed a theory that describes all possible sector geometries. Our theory unifies local and global competitions without assuming any particular mechanism for growth and dispersal. Although mechanism-free, the theory makes quantitative predictions, which we confirmed experimentally. We also simulated specific microscopic models to demonstrate that the takeover by a mutant with a slower monoculture expansion velocity is generic and could occur due to multiple ecological mechanisms. These simulations further confirmed that sector-shape prediction from geometric theory is universal. Taken together, our results establish a framework to understand evolutionary and ecological dynamics in expanding populations with arbitrary frequency- and density-dependent selection.     

Adhesion GPCR Latrophilin 3 regulates synaptic function of cone photoreceptors in a trans-synaptic manner

Cone photoreceptors mediate daylight vision in vertebrates. Changes in neurotransmitter release at cone synapses encode visual information and is subject to precise control by negative feedback from enigmatic horizontal cells. However, the mechanisms that orchestrate this modulation are poorly understood due to a virtually unknown landscape of molecular players. Here, we report a molecular player operating selectively at cone synapses that modulates effects of horizontal cells on synaptic release. Using an unbiased proteomic screen, we identified an adhesion GPCR Latrophilin3 (LPHN3) in horizontal cell dendrites that engages in transsynaptic control of cones. We detected and characterized a prominent splice isoform of LPHN3 that excludes a element with inhibitory influence on transsynaptic interactions. A gain-of-function mouse model specifically routing LPHN3 splicing to this isoform but not knockout of LPHN3 diminished Ca_V1.4 calcium channel activity profoundly disrupted synaptic release by cones and resulted in synaptic transmission deficits. These findings offer molecular insight into horizontal cell modulation on cone synaptic function and more broadly demonstrate the importance of alternative splicing in adhesion GPCRs for their physiological function.

Vision is a key sensory modality essential for the survival of most living organisms. In mammals, it is enabled by the retina: a neural structure composed of more than 60 distinct neurons each uniquely wired into the circuitry and with particular roles in image processing (1, 2). Vision begins with the detection of light by rod and cone photoreceptors. Rod photoreceptor cells are exquisitely sensitive to light and mediate vision at low light levels (3, 4). However, most vertebrates including humans rely on cone cells for daytime vision (5). Accordingly, cones have an extremely broad range of light sensitivity spanning 6 to 7 orders of magnitude (6), quickly adapting to changes in luminance and providing high spatial and temporal visual acuity (5, 7, 8). The molecular, cellular, and circuit mechanisms that allow cones to perform their tasks has been a subject of intense interest, providing groundbreaking discoveries that illuminate fundamental organizational principles that govern signal processing by neural circuits in general.The capture and processing of photons by the phototransduction cascade of cones generates graded changes in membrane potential: hyperpolarizing to light and depolarizing with darkness (7). These voltage signals alter the ongoing rate of neurotransmitter glutamate release at the cone synapse to relay information about light and dark to the retinal circuitry (9). The molecular entity that mediates this transformation is the L-type voltage-gated Ca²⁺ channel, Ca_V1.4 (10–12). It is located at specialized active zones containing synaptic ribbons and couples light-driven changes in voltage to changes in local Ca²⁺ levels thereby regulating the vesicular fusion machinery (13, 14). The Ca_V1.4 channel forms a macromolecular complex with a number of synaptic molecules and thus plays a pivotal role in both the structural and functional organization of the presynaptic active zone of photoreceptors (15). Accordingly, changes in Ca_V1.4 function imposed by binding partners or environment have a tremendous impact on the synaptic communication of cone photoreceptors and vision (16–18).Cones form synaptic contacts with three types of neurons. They synapse with postsynaptic ON- and OFF-type bipolar cells (BC) to relay visual information to the downstream neuronal circuitry (19, 20). Cones also contact lateral inhibitory neurons known as horizontal cells (HCs) that connect adjacent to BC dendrites, forming a tripartite synaptic triad (20). This elaborate synaptic arrangement of cones is a site of major influence on how visual information is processed contributing to unique cone physiology and adaptive capacity for daylight detection (21, 22).The function of HCs and their physiological mechanisms are particularly intriguing. HCs powerfully modulate synaptic transmission at cone synapses (23). Light-evoked hyperpolarization of HCs counteracts light-induced suppression of glutamate release from cone terminals, thereby providing strong negative feedback (23, 24). Because each HC contacts multiple cones, this negative influence on surrounding cones is a major mechanism for producing lateral inhibition, a classical feature of signal processing in the retina that enhances contrast and spatial resolution of vision (25). In addition, feedback from individual HC dendrites to specific cone terminals and ribbons can also act locally, fine-tuning synaptic output to local illumination gradients (26–29).While the role of HCs from a circuit perspective is well understood, the mechanisms that they use to provide negative feedback are subject to debate and controversy. At least three different explanations have been provided: direct ephaptic effects (30, 31), changes in synaptic pH (28, 32, 33), and modulation by GABA released from HCs (34, 35). These models are not necessarily mutually exclusive and unifying theories have been proposed (35, 36). Importantly, one of the central effects invariably observed in response to HC feedback is modulation of the Ca_V1.4 function at the active zones of cone terminals (32, 37). However, there is a significant void in our understanding of molecular mechanisms by which HCs modulate transmission of cone signals, mostly due to a paucity of players known to operate at this synapse. Identification and functional characterization of molecular elements involved in coordinating HC influence in cone synapses can transform our understanding of this enigmatic area of visual neuroscience.Here, we performed an unbiased proteomic profiling of proteins selectively enriched in cone synapses. This led to identification of an adhesion G protein–coupled receptor (aGPCR), latrophilin3 (LPHN3), whose role in retina physiology, photoreceptor synaptic development, and function was previously unexplored. We show that alternative splicing of LPHN3 in the retina generates unique isoforms with distinct properties. Using mouse models, we demonstrate that changes in LPHN3 splicing regulate cone synaptic transmission transsynaptically by affecting Ca_V1.4 function. These findings reveal a molecular player with a pivotal role in regulating synaptic function of cone photoreceptors.