Control of G protein-coupled receptor function via membrane-interacting intrinsically disordered C-terminal domains.

G protein-coupled receptors (GPCRs) control intracellular signaling cascades via agonist-dependent coupling to intracellular transducers including heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. In addition to their critical interactions with the transmembrane core of active GPCRs, all three classes of transducers have also been reported to interact with receptor C-terminal domains (CTDs). An underexplored aspect of GPCR CTDs is their possible role as lipid sensors given their proximity to the membrane. CTD-membrane interactions have the potential to control the accessibility of key regulatory CTD residues to downstream effectors and transducers. Here we report that the CTDs of two closely related family C GPCRs, metabotropic glutamate receptor 2 (mGluR2) and mGluR3, bind to membranes and that this interaction controls receptor function. We first characterize CTD structure with NMR spectroscopy, revealing lipid composition-dependent modes of membrane binding. Using molecular dynamics simulations and structure-guided mutagenesis, we identify key conserved residues and cancer-associated mutations that control CTD-membrane binding. Finally, we provide evidence that mGluR3 transducer coupling is controlled by CTD-membrane interactions in live cells which can be modulated by disease-associated mutations or CTD phosphorylation. This work reveals a novel mechanism of GPCR modulation, suggesting that CTD-membrane binding may be a general regulatory mode throughout the broad GPCR superfamily.

Prognosis and Interplay of Cognitive Impairment and Sarcopenia in Older Adults Discharged from Acute Care Hospitals.

Sarcopenia and cognitive impairment are associated with an increased risk of negative outcomes, but their prognostic interplay has not been investigated so far. We aimed to investigate the prognostic interaction of sarcopenia and cognitive impairment concerning 12-month mortality among older patients discharged from acute care wards in Italy. Our series consisted of 624 patients (age = 80.1 ± 7.0 years, 56.1% women) enrolled in a prospective observational study. Sarcopenia was defined following the European Working Group on Sarcopenia in Older People (EWGSOP) criteria. Cognitive impairment was defined as age- and education-adjusted Mini-Mental State Examination (MMSE) score < 24 or recorded diagnosis of dementia. The study outcome was all-cause mortality during 12-month follow-up. The combination of sarcopenia and cognitive ability was tested against participants with intact cognitive ability and without sarcopenia. Overall, 159 patients (25.5%) were identified as having sarcopenia, and 323 (51.8%) were cognitively impaired. During the follow-up, 79 patients (12.7%) died. After adjusting for potential confounders, the combination of sarcopenia and cognitive impairment has been found associated with increased mortality (HR = 2.12, 95% CI = 1.05-4.13). Such association was also confirmed after excluding patients with dementia (HR = 2.13, 95% CI = 1.06-4.17), underweight (HR = 2.18, 95% CI = 1.03-3.91), high comorbidity burden (HR = 2.63, 95% CI = 1.09-6.32), and severe disability (HR = 2.88, 95% CI = 1.10-5.73). The co-occurrence of sarcopenia and cognitive impairment may predict 1-year mortality in older patients discharged from acute care hospitals.

Plasma aldosterone is increased in class 2 and 3 obese essential hypertensive patients despite drug treatment.

BACKGROUND: The aim of this study was to evaluate whether body mass index (BMI) is independently correlated with plasma aldosterone concentration (PAC) in treated essential hypertensive patients, and whether the relationship between BMI and high blood pressure (BP) can be partially mediated by PAC despite renin-angiotensin-aldosterone system blockade. METHODS: This study used a cross-sectional design and included 295 consecutive essential hypertensive patients referred to our centre for uncontrolled BP despite stable antihypertensive treatment for at least 6 months. The main exclusion criteria were age >65 years; glomerular filtration rate <30 ml/min; and therapy with mineralocorticoid receptor antagonists, direct renin inhibitors, amiloride or oral contraceptives. RESULTS: Higher levels of obesity showed a significantly higher mean PAC with a steep nonlinear increase in patients with BMI ≥ 35 kg/m(2). Class 2 and 3 obese patients had a higher mean PAC than nonobese and class 1 obese patients, even in patients under stable treatment with either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). In a stepwise multiple linear regression model, only log of plasma renin activity (PRA), mean blood pressure (MBP), and class 2 and 3 obesity showed an independent correlation with PAC. In the same model applied to patients treated with ACEIs or ARBs, only logPRA and class 2 and 3 obesity showed a direct correlation with PAC. CONCLUSIONS: In treated essential hypertensive patients, a BMI ≥ 35 kg/m(2) is independently, albeit modestly, correlated with PAC. The correlation between BMI ≥ 35 kg/m(2) and PAC holds true even in ACEI/ARB-treated patients. Further study is required to determine whether the association of obesity with BP is mediated by PAC in hypertensive patients on stable therapy with ACEIs or ARBs.

The association of left ventricular hypertrophy with metabolic syndrome is dependent on body mass index in hypertensive overweight or obese patients.

BACKGROUND: Overweight (Ow) and obesity (Ob) influence blood pressure (BP) and left ventricular hypertrophy (LVH). It is unclear whether the presence of metabolic syndrome (MetS) independently affects echocardiographic parameters in hypertension. METHODS: 380 Ow/Ob essential hypertensive patients (age ≤ 65 years) presenting for referred BP control-related problems. MetS was defined according to NCEP III/ATP with AHA modifications and LVH as LVM/h(2.7) ≥ 49.2 g/m(2.7) in males and ≥ 46.7 g/m(2.7) in females. Treatment intensity score (TIS) was used to control for BP treatment as previously reported. RESULTS: Hypertensive patients with MetS had significantly higher BMI, systolic and mean BP, interventricular septum and relative wall thickness and lower ejection fraction than those without MetS. LVM/h(2.7) was significantly higher in MetS patients (59.14 ± 14.97 vs. 55.33 ± 14.69 g/m(2.7); p = 0.022). Hypertensive patients with MetS had a 2.3-fold higher risk to have LVH/h(2.7) after adjustment for age, SBP and TIS (OR 2.34; 95%CI 1.40-3.92; p = 0.001), but MetS lost its independent relationship with LVH when BMI was included in the model. CONCLUSIONS: In Ow/Ob hypertensive patients MetS maintains its role of risk factor for LVH independently of age, SBP, and TIS, resulting in a useful predictor of target organ damage in clinical practice. However, MetS loses its independent relationship when BMI is taken into account, suggesting that the effects on MetS on LV parameters are mainly driven by the degree of adiposity.

Microalbuminuria and left ventricular mass in overweight and obese hypertensive patients: role of the metabolic syndrome.

BACKGROUND: Left ventricular hypertrophy (LVH) and microalbuminuria are common in hypertensive patients and are often associated with metabolic syndrome (MetS). However, it is not clear whether MetS could modify the association between cardiac and renal damage. OBJECTIVE: The aim of this study was to assess if the relationship of albumin/creatinine ratio (ACR) and left ventricular mass (LVM) could be independent from MetS in hypertensive overweight/obese patients. METHODS: 180 essential hypertensive and overweight/obese (body mass index [BMI] ≥25 kg/m(2)) patients referred to our Hypertension Centre from January 2006 to April 2009 because of blood pressure (BP) control-related problems were studied. Exclusion criteria were scarce adherence to antihypertensive drug therapy as investigated by the Morisky Medical Adherence Scale (MMAS), heart failure (New York Heart Association III or IV or left ventricular ejection fraction [LVEF] <50%), liver failure, cancer or other systemic severe diseases. MetS was defined according to the National Cholesterol Education Program (USA) Adult Treatment Panel III classification as modified by the American Heart Association. ACR was obtained from first morning urine specimens. Left ventricular dimensions, mass and ejection fraction, were measured by echocardiography following the American Society of Echocardiography recommendations. RESULTS: Patients with microalbuminuria had a 6-fold higher risk for LVH/h(2.7) and 2-fold higher risk for LVH/body surface area (BSA). Univariate linear regression analysis showed a positive relationship between ACR and LVM, expressed both as LVM/h(2.7) or LVM/BSA, as well as a direct correlation between logACR and interventricular diameters and ejection fraction. Regression models including logACR, estimated glomerular filtration rate, BMI, age, hypertension duration, smoking and MetS (as a single variable as well as each single component), showed that only logACR, BMI, hypertension duration and systolic blood pressure (SBP) were independently associated with LVM/h(2.7). CONCLUSION: Along with BP and BMI, albuminuria measured in a morning urine sample as ACR is a valuable low-cost index of cardiac organ damage and increased cardiovascular risk in hypertensive patients independently by MetS. On the other hand, MetS is not an independent risk factor for cardiac damage because it does not seem to add anything more than the sum of each of its components (especially SBP and adiposity indexed by BMI) to the relationship between cardiac and renal subclinical organ damage.

Cannabinoid CB1 receptor expression in relation to visceral adipose depots, endocannabinoid levels, microvascular damage, and the presence of the Cnr1 A3813G variant in humans.

Dysregulation of the endocannabinoid system in the visceral adipose tissue (VAT) is associated with metabolic and cardiovascular complications of obesity. We studied perirenal VAT CB1 receptor expression in relation to anthropometry, VAT area and endocannabinoid levels, kidney microvascular damage (MVDa), and the presence of the CB1 gene A3813G variant, the frequency of which was also evaluated in a large population of obese-hypertensive (OH) patients with or without the metabolic syndrome (MetS). Perirenal VAT and kidney samples were obtained from 30 patients undergoing renal surgery. Total and perirenal VAT areas were determined by computed tomography. CB1 messenger RNA expression and endocannabinoid levels in perirenal VAT were determined by quantitative reverse transcriptase polymerase chain reaction and liquid chromatography-mass spectrometry, respectively. The MVDa was evaluated in healthy portions of kidney cortex. The A3813G alleles were identified by genotyping in these patients and in 280 nondiabetic OH patients (age

A manual of guidelines to score the modified cumulative illness rating scale and its validation in acute hospitalized elderly patients.

OBJECTIVES: To update previous guidelines to score the Cumulative Illness Rating Scale (CIRS) and test their usefulness in hospitalized elderly patients. DESIGN: The CIRS was scored retrospectively in a cohort of elderly patients followed for 18 months. SETTING: An acute internal medicine ward in an academic tertiary care hospital. PARTICIPANTS: Three hundred eighty-seven patients aged 65 and older. MEASUREMENTS: The CIRS was retrospectively scored for the enrolled patients. Intrarater and interrater reliability were calculated. Two illness severity indices (total score (TSC) and severity (SV)) and one comorbidity index (CM) were obtained. Clinical features and comprehensive geriatric assessment (CGA) variables were also used. All patients underwent an 18-month follow-up for mortality and rehospitalization. RESULTS: Intrarater and interrater reliability of the CIRS scored following the guidelines was good (intraclass correlation coefficients of 0.83 and 0.81, respectively). The TSC, SV, and CM correlated with clinical features (laboratory values, medication usage, and length of in-hospital stay) and CGA variables (cognitive impairment, depression and disability). All three indices were able to predict 18-month mortality and rehospitalization rates. CONCLUSION: This study confirmed the validity of the CIRS as an indicator of health status and demonstrated its ability to predict 18-month mortality and rehospitalization in hospitalized elderly patients. The availability of detailed guidelines for scoring the CIRS can improve its usefulness and facilitate more-widespread use for research and clinical aims.

A human fatty acid amide hydrolase (FAAH) functional gene variant is associated with lower blood pressure in young males.

BACKGROUND: Fatty acid amide hydrolase (FAAH) inhibitors, preventing endocannabinoid (EC) degradation, reduce blood pressure (BP) and heart rate in young male (YM) hypertensive rodents. The functional human FAAH 129T gene variant results in reduced protein level and enzymatic activity but its relationship with BP is unknown. This study investigates the relationship among FAAH P129T alleles and cardiovascular features in YMs at baseline and after 9-year follow-up, and in older male obese hypertensive (OH) patients, in whom the EC system (ECS) is overactive. METHODS: Genotype analysis was performed in 215 Caucasian male students (24 (0.2) years old) and in 185 older OH patients (50 (0.2) years old). YMs were also followed up for 9 years. Clinical and anthropometric variables, BP, cardiac and carotid artery echographic measurements were evaluated. RESULTS: YMs with the FAAH 129T allele had lower systolic (P = 0.042) and mean BP (P = 0.022), and a trend toward lower diastolic BP (P = 0.06). Such significant association was maintained at follow-up. In contrast, the same allele was not associated with BP in older OH. No association was found with other cardiac and vascular variables. CONCLUSION: An FAAH defective gene variant results in lower BP in YMs, similar to the findings in young rodents. This effect is lost in older OH patients. Because cannabinoid CB1 receptor blockade is associated with BP reduction in OH patients, EC effects and the use of ECS-interfering drugs is likely to be age and clinical-condition dependent.