Despite the central physiological function of the myogenic response, the underlying signalling pathways and the identity of mechanosensors in vascular smooth muscle (VSM) are still elusive. In contrast to present thinking, we show that membrane stretch does not primarily gate mechanosensitive transient receptor potential (TRP) ion channels, but leads to agonist-independent activation of G q/11 -coupled receptors, which subsequently signal to TRPC channels in a G protein-and phospholipase C-dependent manner. Mechanically activated receptors adopt an active conformation, allowing for productive G protein coupling and recruitment of b-arrestin. Agonistindependent receptor activation by mechanical stimuli is blocked by specific antagonists and inverse agonists. Increasing the AT 1 angiotensin II receptor density in mechanically unresponsive rat aortic A7r5 cells resulted in mechanosensitivity. Myogenic tone of cerebral and renal arteries is profoundly diminished by the inverse angiotensin II AT 1 receptor agonist losartan independently of angiotensin II (AII) secretion. This inhibitory effect is enhanced in blood vessels of mice deficient in the regulator of G-protein signalling-2. These findings suggest that G q/11 -coupled receptors function as sensors of membrane stretch in VSM cells.

ObjectiveThis analysis explored the association of treatment adherence with beliefs about medication, patient demographic and disease characteristics and medication types in rheumatoid arthritis (RA), psoriatic arthritis (PsA) or ankylosing spondylitis (AS) to develop adherence prediction models.MethodsThe population was a subset from ALIGN, a multicountry, cross-sectional, self-administered survey study in adult patients (n=7328) with six immune-mediated inflammatory diseases who were routinely receiving systemic therapy. Instruments included Beliefs about Medicines Questionnaire (BMQ) and 4-item Morisky Medication Adherence Scale (MMAS-4©), which was used to define adherence.ResultsA total of 3390 rheumatological patients were analysed (RA, n=1943; PsA, n=635; AS, n=812). Based on the strongest significant associations, the adherence prediction models included type of treatment, age, race (RA and AS) or disease duration (PsA) and medication beliefs (RA and PsA, BMQ-General Harm score; AS, BMQ-Specific Concerns score). The models had cross-validated areas under the receiver operating characteristic curve of 0.637 (RA), 0.641 (PsA) and 0.724 (AS). Predicted probabilities of full adherence (MMAS-4©=4) ranged from 5% to 96%. Adherence was highest for tumour necrosis factor inhibitors versus other treatments, older patients and those with low treatment harm beliefs or concerns. Adherence was higher in white patients with RA and AS and in patients with PsA with duration of disease <9 years.ConclusionsFor the first time, simple medication adherence prediction models for patients with RA, PsA and AS are available, which may help identify patients at high risk of non-adherence to systemic therapies.Trial registration numberACTRN12612000977875.

IntroductionMedication adherence is critical in chronic immune-mediated inflammatory diseases (IMIDs) and could be affected by patients’ treatment-related beliefs. The objective of this study was to determine beliefs about systemic medications in patients with IMIDs and to explore the association of those beliefs and other factors with adherence.MethodsThis was a multi-country, cross-sectional, self-administered survey study. Included were adults diagnosed with one of six IMIDs receiving conventional systemic medications and/or tumor necrosis factor inhibitors (TNFi). Patients’ necessity beliefs/concerns towards and adherence to treatments were assessed by the Beliefs about Medicines Questionnaire and four-item Morisky Medication Adherence Scale. Correlation of patients’ beliefs about treatment and other factors with adherence were evaluated by multivariable regression analyses.ResultsAmong studied patients (N = 7197), 32.0% received TNFi monotherapy, 27.7% received TNFi–conventional combination therapy, and 40.3% received conventional medications. Across IMIDs, high adherence to systemic treatment was more prevalent in TNFi groups (61.3–80.7%) versus corresponding conventional treatment groups (28.4–64.7%). In at least four IMIDs, greater perception of the illness continuing forever (P < 0.001), of the treatment helping (P < 0.001), and more concerns about the illness (P < 0.01), but not clinical parameters, were associated with higher treatment necessity beliefs. Higher treatment necessity beliefs, older age, Caucasian race, and TNFi therapy were associated with high medication adherence in at least four IMIDs.ConclusionsTreatment necessity beliefs were higher than concerns about current medication in patients with IMID. Illness perceptions had a greater impact on treatment necessity beliefs than clinical parameters. Older age, greater treatment necessity beliefs, and TNFi therapy were associated with high self-reported medication adherence in at least four IMIDs.Trial registrationACTRN12612000977875.FundingAbbVie.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-016-0441-3) contains supplementary material, which is available to authorized users.

Glycoprotein hormone receptors such as the lutropin/chorionic gonadotropin receptor (LHR) are characterized by a large N-terminal ectodomain (ECD), which is responsible for hormone-receptor interactions. For the closely related TSH receptor (TSHR), it has been proposed that the ECD also serves as a tethered inverse agonist. However, the exact role of the LHR-ECD for receptor activation remains elusive. Functional analysis of N-terminally truncated LHR mutants expressed in COS-7 cells revealed that the LHR-ECD does not act as an inverse agonist but facilitates active LHR conformations. This notion is supported by two observations: first, removal of the ECD tended to decrease basal LHR activity and secondly, mutationally induced constitutive receptor activity was diminished for most activating mutations in LHR lacking the ECD. In addition, swapping of the LHR-ECD for the ECD of the closely related TSHR was not sufficient to restore constitutive receptor activity induced by naturally occurring activating heptahelical LHR mutations. Thus, the ECD stabilizes an activation-competent conformation of the heptahelical region. While the full-length LHR fused to the cognate agonist, human chorionic gonadotropin (hCG), showed increased basal activity, fusion proteins between hCG and Nterminally truncated LHR did not yield constitutive receptor activity suggesting an important role of the ECD also for agonist-dependent LHR activity. Our experiments strengthen the concept of a major contribution of the LHR-ECD in the activation mechanism apart from hormone binding and provide evidence for a cooperative model with structural and functional interactions of the ECD and the transmembrane domain.

The receptors for the trophic hormones luteinizing hormone (LH), follicle-stimulating hormone (FSH), and thyrotropin (TSH) play a central role in endocrinology. These receptors face the challenge to accommodate large heterodimeric glycoprotein ligands within their extracellular hormone-binding domain. Until recently, the mechanism of hormone binding and consequently the mode of receptor activation remained enigmatic. By solving the crystal structure of human follicle-stimulating hormone bound to the receptor's hormone binding domain, it has become clear that the follicle-stimulating hormone receptor grabs the glycoprotein hormone in a hand-clasp mode resulting in a hormone orientation perpendicular to the long axis of the ligand-binding domain. These findings have important ramifications for our understanding of the molecular mechanism of receptor activation and may provide a rational basis for the development of small, non-peptidic FSH receptor ligands.