Metabotropic glutamate receptors are class C G-protein-coupled receptors which respond to the neurotransmitter glutamate. Structural studies have been restricted to the amino-terminal extracellular domain, providing little understanding of the membrane-spanning signal transduction domain. Metabotropic glutamate receptor 5 is of considerable interest as a drug target in the treatment of fragile X syndrome, autism, depression, anxiety, addiction and movement disorders. Here we report the crystal structure of the transmembrane domain of the human receptor in complex with the negative allosteric modulator, mavoglurant. The structure provides detailed insight into the architecture of the transmembrane domain of class C receptors including the precise location of the allosteric binding site within the transmembrane domain and key micro-switches which regulate receptor signalling. This structure also provides a model for all class C G-protein-coupled receptors and may aid in the design of new small-molecule drugs for the treatment of brain disorders.

Inositol 1,4,5-trisphosphate receptors (InsP3R) and ryanodine receptors (RyR) are tetrameric intracellular Ca2+ channels1. For each, the pore is formed by C-terminal transmembrane domains and regulated by signals detected by the large cytosolic structures. InsP3R gating is initiated by InsP3 binding to the InsP3-binding core (IBC, residues 224-604 of InsP3R1)2 and it requires the suppressor domain (SD, residues 1-223)2-8. We present structures of the N-terminal region (NT) of InsP3R1 with (3.6 Å) and without (3.0 Å) InsP3 bound. The arrangement of the three NT domains, the SD, IBC-β and IBC-α, identifies two discrete interfaces (α and β) between the IBC and SD. Similar interfaces occur between equivalent domains (A, B and C) in RyR19. The orientations of the three domains docked into a tetrameric structure of InsP3R10 and of the ABC domains in RyR9 are remarkably similar. The importance of the α-interface for activation of InsP3R and RyR is confirmed by mutagenesis and, for RyR, by disease-causing mutations9,11,12. InsP3 causes partial closure of the clam-like IBC, disrupting the β-interface and pulling the SD towards the IBC. This reorients an exposed SD loop (HS-loop) that is essential for InsP3R activation7. The loop is conserved in RyR and includes mutations associated with malignant hyperthermia and central core disease9,11,12. The HS-loop interacts with an adjacent NT, suggesting that activation re-arranges inter-subunit interactions. The A-domain of RyR functionally replaced the SD in a full-length InsP3R, and an InsP3R in which its C-terminal transmembrane region was replaced by that from RyR1 was gated by InsP3 and blocked by ryanodine. Activation mechanisms are conserved between InsP3R and RyR. Allosteric modulation of two similar domain interfaces within an N-terminal subunit re-orients the first domain (SD or A-domain), allowing it, via interactions of the second domain of an adjacent subunit (IBC-β or B-domain), to gate the pore.

The current results provide one of the few demonstrations of a single stress episode producing sustained enhancement of ASR. In addition, topiramate demonstrates promise in treating exaggerated acoustic startle symptoms in PTSD or other stress-related disorders.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may play a role in panic disorder. HPA studies in patients with panic disorder, however, have produced inconsistent results. Seeking to understand the inconsistencies, we reexamined endocrine data from four studies of patients with panic disorder, in light of animal data highlighting the salience of novelty, control, and social support to HPA axis activity. Patients with panic disorder were studied (1) at rest over a full circadian cycle, (2) before and after activation by a panicogenic respiratory stimulant (doxapram) that does not directly stimulate the HPA axis, and (3) before and after a cholecystokinin B (CCK-B) agonist that is panicogenic and does directly stimulate the HPA axis. Patients with panic disorder had elevated overnight cortisol levels, which correlated with sleep disruption. ACTH and cortisol levels were higher in a challenge paradigm (doxapram) than in a resting state study, and paradigm-related ACTH secretion was exaggerated in patients with panic disorder. Panic itself could be elicited without HPA axis activation. Patients with panic disorder showed an exaggerated ACTH response to pentagastrin stimulation, but this response was normalized by prior exposure to the experimental context or psychological preparation to reduce novelty and enhance sense of control. Novelty is one of a number of contextual cues known from animal work to activate the HPA axis. The HPA axis abnormalities seen in patients with panic disorder in the four experiments reviewed here might all be due to exaggerated HPA axis reactivity to novelty cues. Most of the published panic/HPA literature is consistent with the hypothesis that HPA axis dysregulation in panic is due to hypersensitivity to contextual cues. This hypothesis requires experimental testing. Depression and Anxiety 24:66-76,

BackgroundTofacitinib (CP-690,550) is a novel Janus kinase inhibitor in development as an oral formulation for the treatment of several inflammatory diseases including psoriasis.ObjectivesThis phase 2a study aimed to assess the efficacy, systemic safety, local tolerability and systemic pharmacokinetics of topical tofacitinib in mild-to-moderate plaque psoriasis.MethodsTwo tofacitinib ointment formulations were evaluated in this multicentre, double-blind, vehicle-controlled trial (NCT01246583). Seventy-one patients were randomized 2 : 1 : 2 : 1 to 2% tofacitinib ointment 1, vehicle 1, 2% tofacitinib ointment 2 and vehicle 2, each administered twice daily for 4 weeks to a single fixed 300 cm2 treatment area containing a target plaque with or without one or more nontarget plaques and normal skin.ResultsThe primary endpoint of percentage change from baseline in the Target Plaque Severity Score at week 4 demonstrated statistically significant improvement for ointment 1 [least squares mean (LSM) –54·4%] vs. vehicle 1 (LSM –41·5%), but not ointment 2 (LSM –24·2%) vs. vehicle 2 (LSM –17·2%). Secondary endpoints (target plaque area and Itch Severity Item) improved similarly for tofacitinib ointment vs. corresponding vehicle. Adverse event (AE) occurrence was similar across treatment groups. All AEs were mild or moderate and none were serious or led to subject discontinuation. One application-site AE (erythema) was reported. Tofacitinib mean systemic exposure was minimal and was greater for ointment 1 than for ointment 2.ConclusionsTofacitinib ointment 1 was well tolerated and efficacious compared with vehicle for the treatment of plaque psoriasis. Further study of topical tofacitinib for psoriasis treatment is warranted.

Eosinophilic gastroenteritis is a heterogeneous and uncommon disorder characterized by eosinophilic inflammation of the gastrointestinal tissues. The location and depth of infiltration determine its varied manifestations, and the latter is also the basis for the proposed classification into mucosal, muscular and serosal eosinophilic gastroenteritis. Abdominal pain, vomiting, and diarrhea are each present in nearly 50% of the patients, with some overlap. Peripheral eosinophilia is seen in approximately two-thirds of patients with eosinophilic gastroenteritis. It is now clear that eotaxin, a specific eosinophil chemoattractant, plays a pivotal role in the process of eosinophil production. The differential diagnosis of eosinophilic gastroenteritis in children includes parasitic infections, inflammatory bowel disease, connective tissue diseases, some malignancies and adverse effects of drugs. Eosinophilic gastroenteritis itself has been strongly associated with food allergies, and concomitant atopic diseases or a family history of allergies is elicited in about 70% of cases. The pediatric experience is unique with respect to recognition of distinctive entities such as allergic procto-colitis, almost exclusively seen in infants, and eosinophilic esophagitis being increasingly reported among children and young adults. The gold standard for diagnosis, usually demonstrated on endoscopic biopsies, is prominent tissue eosinophilia. However, the diagnosis may be obscured by the patchy nature of the disease, and muscular and serosal eosinophilic gastroenteritis subtypes. In the latter cases, full thickness biopsies would be indicated for a definitive diagnosis. There are many reports of successful treatment of eosinophilic gastroenteritis in children, using a variety of treatment regimens including elimination diets. Corticosteroids remain the most effective agents for controlling symptoms, but unfortunately the relapsing nature of the disease would mandate prolonged corticosteroid use. Reports of favorable responses to new leukotriene inhibitors in patients with eosinophilic gastroenteritis are encouraging; these responses should stimulate future research on the pathophysiology and management of eosinophilic gastroenteritis.

Eosinophilic gastroenteritis is an infrequently diagnosed condition that is characterized by prominent eosinophilic infiltration of the stomach or small intestine, generally localized to one level of the intestinal wall; the variable organ locus and wall depth produce heterogeneous clinical presentations. A strong association with atopy is present in most cases, supported by circumstantial evidence and the demonstration of Th-2 proinflammatory cytokine profiles in animal studies. A high degree of suspicion is required to establish the diagnosis, which must be based on intense gastrointestinal eosinophilia. Management is directed toward removal of offending allergens and use of anti-inflammatory agents. Novel and emerging treatments on the horizon are biologic therapies and selective anti-eosinophil agents.

SummaryBackground-There is considerable anecdotal and some scientific evidence that stress triggers eating behavior, but underlying physiological mechanisms remain uncertain. The hypothalamicpituitary-adrenal (HPA) axis is a key mediator of physiological stress responses and may play a role in the link between stress and food intake. Cortisol responses to laboratory stressors predict consumption but it is unclear whether such responses mark a vulnerability to stress-related eating or whether cortisol directly stimulates eating in humans.