The metabotropic glutamate receptor (mGluR) 4 subtype of metabotropic glutamate receptor is a presynaptic receptor that modulates neurotransmitter release. We have characterized the properties of a truncated, epitope-tagged construct containing part of the extracellular amino-terminal domain of mGluR4. The truncated receptor was secreted into the cell culture medium of transfected human embryonic kidney cells. The oligomeric structure of the soluble truncated receptor was assessed by gel electrophoresis. In the presence of high concentrations of a reducing agent, the truncated receptor migrated as a monomer; at lower concentrations of the reducing agent, only higher molecular weight oligomers were observed. Competition binding experiments using the radiolabeled agonist [ 3 H]L-2-amino-4-phosphonobutyric acid revealed that the rank order of potency of metabotropic ligands at the truncated receptor was similar to that of the full-length membrane-bound receptor. However, the truncated receptor displayed higher affinities for agonists and lower affinities for antagonists compared with the full-length receptor. Deglycosylation produced a shift in the relative molecular weight of the soluble protein from M r ‫؍‬ 71,000 to M r ‫؍‬ 63,000; deglycosylation had no effect on the binding of [ 3 H]L-2-amino-4-phosphonobutyric acid, indicating that the asparagine-linked carbohydrates are not necessary for agonist binding. These results demonstrate that although the primary determinants of ligand binding to mGluR4 are contained within the first 548 amino acids of the receptor, additional amino acids located downstream of this region may influence the affinity of ligands for the binding site. The metabotropic glutamate receptors (mGluRs)1 are a family of neurotransmitter receptors that mediate a variety of physiological functions in the central nervous system including the modulation of synaptic transmission. The mGluR family of receptors has been divided into three subgroups based on sequence homology, signal transduction properties, and pharmacological profiles (1, 2). Group I mGluRs include mGluR1 and mGluR5 and are coupled to the stimulation of phosphoinositol turnover. Group II receptors include mGluR2 and mGluR3, and group III receptors include mGluR4, mGluR6, mGluR7, and mGluR8. In cell lines, group II and III mGluRs couple to the inhibition of cAMP formation. The mGluRs are homologous with the calcium-sensing receptors, the GABA B receptors, and a class of mammalian pheromone receptors (2). Within the family of mGluRs, the amino acid sequence identity among members of a subgroup is approximately 70%, whereas the homology between the different groups is about 45%.The basic structural domains of mGluRs include a large extracellular amino-terminal domain (ATD), a hydrophobic region containing seven putative transmembrane domains, and an intracellular carboxyl terminus. A molecular model of the tertiary structure of the ATD of the mGluR1 subtype of mGluR has been formulated based on the sequence similarity between the mGluR...

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BackgroundSystemic sclerosis (SSc) is a rare disabling connective tissue disease with few available treatment options. Diffuse cutaneous systemic sclerosis (dcSSc) is associated with high mortality. A previous experiment has shown that JAK2 inhibitor can significantly improve skin fibrosis in bleomycin (BLM)-induced murine model, including reducing dermal thickening and collagen accumulation. We aimed to describe the efficacy of oral JAK1/2 inhibitor baricitinib in SSc patients, especially focusing on skin fibrosis and microvascular manifestations.MethodsWe described the different effects of oral selective JAK1, JAK2, or JAK3 inhibitor treatment in a BLM-induced skin fibrosis mouse model. Furthermore, 10 adult patients with dcSSc were treated with baricitinib. We assessed the changes in modified rodman skin score (mRSS) and digital ulcer net burden at week 12 and 24 from baseline. We also compared the absolute changes in scores on the Scleroderma Health Assessment Questionnaire (SHAQ) and a total score on the St. George's Respiratory Questionnaire (SGRQ) over a 24-week period.ResultsIn the experimental mouse model of skin fibrosis, a JAK1 and JAK2 inhibitor ameliorated skin fibrosis, and a JAK2 inhibitor had the most obvious effect. Treatment with the JAK2 inhibitor also blunted the capillary rarefaction. We demonstrated that skin fibrosis and digital ulcers were significantly relieved in 10 SSc patients treated with baricitinib. The mRSS significantly improved at week 12 from baseline, with a mean change in mRSS of −8.3 [95% confidence interval (CI), −12.03 to −4.574; p = 0.0007] and improved greater at week 24 to −11.67 (95% CI, −16.84 to −6.496; p = 0.0008). Among the four patients with digital ulcers (DU), three were completely healed at week 24, the number of ulcers in another patient was significantly reduced, and there was no patient with new ulcers. Only one adverse event (AE) of herpes zoster was observed.ConclusionsOur results indicate that selective JAK1 and JAK2 inhibitor alleviates skin fibrosis, and oral JAK1/2 inhibitor baricitinib is a potentially effective treatment for dcSSc patients with skin fibrosis and DU. Baricitinib was well-tolerated by most patients in this study. Additional large clinical trials are needed to confirm our pilot findings.Chinese Clinical Trial Registry NumberChiCTR2000030995.

Disclaimer: Dr Naik is an associate editor of JAMA Dermatology, but she was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease and affects many organs, seriously threatening the life quality and health of patients. Pathologically, SLE is attributed to the imbalance of pro-inflammatory and regulatory T-cell (Treg) responses, impaired clearance of apoptotic cells, 1 presence of abundant autoantibodies, and immune complexes. 2 Clinically, approximately 25-50% of unselected SLE patients display renal signs and symptoms when they are diagnosed, and approximately 5-20% of patients with lupus nephropathy (LN) develop end-stage renal disease (ESRD) within 10 years. 3 Currently, the standard treatments for SLE include immunosuppressants and anti-inflammatory agents. However, these therapeutic agents usually cause severe side-effects and various complications, including infections, osteoporosis, and cardiovascular diseases. Hence, further understanding the molecular pathogenesis and discovery of new therapeutic targets will be of high significance in development of novel therapies for SLE patients.It is well known that heredity, environment, hormonal, and other factors contribute to the pathogenesis of SLE. Genomewide association study (GWAS) have revealed that single nucleotide polymorphism (SNP) of the interleukin-1 receptor-associated kinase 1 (IRAK1) is associated with the susceptibility of SLE. 4,5