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Daily use of atogepant (a small-molecule, calcitonin gene–related peptide receptor antagonist) at any of three doses resulted in greater reductions in migraine days per month over a period of 12 weeks than did placebo. Nausea and constipation were side effects in approximately 5% of the participants who received atogepant.

Rimegepant, a small molecule calcitonin gene-related peptide receptor antagonist, has shown efficacy in the acute treatment of migraine using a standard tablet formulation. The objective of this trial was to compare the efficacy, safety, and tolerability of a novel orally disintegrating tablet formulation of rimegepant at 75 mg with placebo in the acute treatment of migraine. In this double-blind, randomised, placebo-controlled, multicentre phase 3 trial, adults aged 18 years or older with history of migraine of at least 1 year were recruited to 69 study centres in the USA. Participants were randomly assigned to receive rimegepant (75 mg orally disintegrating tablet) or placebo and instructed to treat a single migraine attack of moderate or severe pain intensity. The randomisation was stratified by the use of prophylactic medication (yes or no), and was carried out using an interactive web response system that was accessed by each clinical site. All participants, investigators, and the sponsor were masked to treatment group assignment. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h postdose. The efficacy analyses used the modified intention-to-treat population, which included all patients who were randomly assigned, had a migraine attack with pain of moderate or severe intensity, took a dose of rimegepant or placebo, and had at least one efficacy assessment after administration of the dose. The safety analyses included all randomly assigned participants who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT03461757, and is closed to accrual. Between Feb 27 and Aug 28, 2018, 1811 participants were recruited and assessed for eligibility. 1466 participants were randomly assigned to the rimegepant (n=732) or placebo (n=734) groups, of whom 1375 received treatment with rimegepant (n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepant n=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tablet was superior to placebo for freedom from pain (21% vs 11%, p<0·0001; risk difference 10, 95% CI 6–14) and freedom from the most bothersome symptom (35% vs 27%, p=0·0009; risk difference 8, 95% CI 3–13). The most common adverse events were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinary tract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant in each treatment group had a transaminase concentration of more than 3 × the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2 × the upper limit of normal were reported. Treated participants reported no serious adverse events. In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns. Biohaven Pharmaceuticals.

Treatment with the oral calcitonin gene–related peptide receptor antagonist rimegepant resulted in freedom from migraine pain 2 hours after the dose in 20% of patients; 12% of the patients who received placebo were pain-free. Freedom from the most bothersome migraine symptom aside from pain 2 hours after the dose was reported in 38% of patients who received rimegepant and 25% who received placebo.

A higher percentage of participants who received the calcitonin gene–related peptide receptor antagonist ubrogepant had freedom from migraine pain and absence of the most bothersome migraine-associated symptom at 2 hours than participants who received placebo.

The adhesion G-protein-coupled receptor (GPCR) latrophilin 3 (ADGRL3) has been associated with increased risk of attention deficit hyperactivity disorder (ADHD) and substance use in human genetic studies. Knockdown in multiple species leads to hyperlocomotion and altered dopamine signaling. Thus, ADGRL3 is a potential target for treatment of neuropsychiatric disorders that involve dopamine dysfunction, but its basic signaling properties are poorly understood. Identification of adhesion GPCR signaling partners has been limited by a lack of tools to acutely activate these receptors in living cells. Here, we design a novel acute activation strategy to characterize ADGRL3 signaling by engineering a receptor construct in which we could trigger acute activation enzymatically. Using this assay, we found that ADGRL3 signals through G12/G13 and Gq, with G12/13 the most robustly activated. Gα 12/13 is a new player in ADGRL3 biology, opening up unexplored roles for ADGRL3 in the brain. Our methodological advancements should be broadly useful in adhesion GPCR research. Among the adhesion receptor class of GPCRs, which are understudied, the adhesion receptor ADGRL3 can be activated by its own tethered agonist and couples to G protein G12/13 and somewhat to Gq.

Post-mating responses play a vital role in successful reproduction across diverse species. In fruit flies, sex peptide binds to the sex peptide receptor, triggering a series of post-mating responses. However, the origin of sex peptide receptor predates the emergence of sex peptide. The evolutionary origins of the interactions between sex peptide and sex peptide receptor and the mechanisms by which they interact remain enigmatic. In this study, we used ancestral sequence reconstruction, AlphaFold2 predictions, and molecular dynamics simulations to study sex peptide–sex peptide receptor interactions and their origination. Using AlphaFold2 and long-time molecular dynamics simulations, we predicted the structure and dynamics of sex peptide–sex peptide receptor interactions. We show that sex peptide potentially binds to the ancestral states of Diptera sex peptide receptor. Notably, we found that only a few amino acid changes in sex peptide receptor are sufficient for the formation of sex peptide–sex peptide receptor interactions. Ancestral sequence reconstruction and molecular dynamics simulations further reveal that sex peptide receptor interacts with sex peptide through residues that are mostly involved in the interaction interface of an ancestral ligand, myoinhibitory peptides. We propose a potential mechanism whereby sex peptide–sex peptide receptor interactions arise from the preexisting myoinhibitory peptides–sex peptide receptor interface as well as early chance events both inside and outside the preexisting interface that created novel sex peptide-specific sex peptide–sex peptide receptor interactions. Our findings provide new insights into the origin and evolution of sex peptide–sex peptide receptor interactions and their relationship with myoinhibitory peptides–sex peptide receptor interactions.

Migraine is one of the most prevalent and disabling diseases worldwide, but until recently, few migraine-specific therapies had been developed. Extensive basic and clinical scientific investigation has provided strong evidence that the neuropeptide calcitonin gene-related peptide (CGRP) has a key role in migraine. This evidence led to the development of small molecule CGRP receptor antagonists and monoclonal antibodies targeting either CGRP or its receptor. Clinical trials investigating these therapies have consistently shown statistically significant efficacy for either the acute or preventive treatment of migraine. No serious safety or tolerability issues have been identified in the trials of the monoclonal antibody therapies. Although the appropriate place of these new migraine-specific therapies relative to other available acute and preventive treatments remains to be determined, a growing body of evidence shows that therapeutic approaches targeting CGRP have the potential to transform the clinical management of migraine.

Nitrogen (N) is a critical nutrient for plants but is often distributed unevenly in the soil. Plants therefore have evolved a systemic mechanism by which N starvation on one side of the root system leads to a compensatory and increased nitrate uptake on the other side. Here, we study the molecular systems that support perception of N and the long-distance signaling needed to alter root development. Rootlets starved of N secrete small peptides that are translocated to the shoot and received by two leucine-rich repeat receptor kinases (LRR-RKs). Arabidopsis plants deficient in this pathway show growth retardation accompanied with N-deficiency symptoms. Thus, signaling from the root to the shoot helps the plant adapt to fluctuations in local N availability.

Pattern Recognition Receptors (PRRs) are a superfamily of receptors that detect molecular structures typical for pathogens and damaged cells and play a crucial role in the proper function of the innate immune system. A particular subgroup of membrane-bound PRRs is represented by the N-formyl peptide receptors (FPRs) that consist of transmembrane G-protein coupled receptors involved in inflammatory responses. FPRs were initially described in immune cells as transducers of chemotactic signals in phagocytes that react to tissue injury. Subsequently, FPRs were also identified in a wide variety of cell types, including cancer cells. Beyond broad cellular distribution, FPRs are also characterized by the ability to bind a variety of ligands with different chemical and biological properties, ranging from natural peptides to synthetic compounds. The binding of FPRs to specific agonists induces a cascade of functional biological events, such as cell proliferation, migration, angiogenesis, and oxidative stress. From all this evidence, it becomes clear that FPRs are multifaceted receptors involved in several pathophysiological processes associated with inflammation. In this review, we provide a comprehensive molecular description of structure-function relationship of FPRs and their pivotal role in the host defense, highlighting the regulatory functions in both the initiation and resolution of inflammation. In addition to their activity as PRRs during innate immune response, we focus on their involvement in pathological conditions, including chronic inflammatory disease, neurodegenerative disorders, and cancer, with special emphasis on FPR targeting as promising therapeutic strategies in the era of precision medicine.

Background and purpose HER‐MES was the first head‐to‐head study of erenumab against topiramate (standard of care). This post hoc analysis of the HER‐MES study evaluated the effect of erenumab versus topiramate on patient‐reported outcomes at week 24. Methods Adult patients with episodic or chronic migraine (n = 777) were randomized (1:1) to monthly subcutaneous erenumab (n = 389) or daily oral topiramate (n = 388). Migraine‐related disability, as measured by the Headache Impact Test 6 (HIT‐6) and Short Form 36 Health Survey version 2 (SF‐36v2), was analysed in the entire study cohort and true completers. Results In the erenumab group (vs. topiramate), significant improvements were reported in Headache Impact Test 6 total scores (composite populations, −10.88 vs. −7.72; true completers, −11.92 vs. −10.61) and a higher proportion of patients achieved a ≥5‐point reduction from baseline with erenumab (composite populations, 72.2% vs. 53.9%; true completers, 79.64% vs. 71.43%). The adjusted mean change from baseline in the SF‐36v2 score was greater with erenumab for both physical component summary (composite population, 5.48 vs. 3.63; true completers, 5.95 vs. 5.23) and mental component summary (composite populations, 1.00 vs. −1.18; true completers, 1.74 vs. −0.33). A higher proportion of patients on erenumab versus topiramate had a ≥5‐point improvement in SF‐36v2 for the physical component summary (composite populations, 47.7% vs. 37.4%; true completers, 52.1% vs. 48.9%) and mental component summary (composite populations, 25.3% vs. 16.8%; true completers, 27.3% vs. 17.7%). Conclusions This post hoc analysis demonstrated that patients treated with erenumab had significant improvements in headache impact and quality of life as measured by patient‐reported outcomes versus patients treated with topiramate.