Decoding the signaling of a GPCR heteromeric complex reveals a unifying mechanism of action of antipsychotic drugs.

Atypical antipsychotic drugs, such as clozapine and risperidone, have a high affinity for the serotonin 5-HT(2A) G protein-coupled receptor (GPCR), the 2AR, which signals via a G(q) heterotrimeric G protein. The closely related non-antipsychotic drugs, such as ritanserin and methysergide, also block 2AR function, but they lack comparable neuropsychological effects. Why some but not all 2AR inhibitors exhibit antipsychotic properties remains unresolved. We now show that a heteromeric complex between the 2AR and the G(i)-linked GPCR, metabotropic glutamate 2 receptor (mGluR2), integrates ligand input, modulating signaling output and behavioral changes. Serotonergic and glutamatergic drugs bind the mGluR2/2AR heterocomplex, which then balances Gi- and Gq-dependent signaling. We find that the mGluR2/2AR-mediated changes in Gi and Gq activity predict the psychoactive behavioral effects of a variety of pharmocological compounds. These observations provide mechanistic insight into antipsychotic action that may advance therapeutic strategies for disorders including schizophrenia and dementia.

Overestimation of aerobic capacity with the bruce treadmill protocol in patients being assessed for suspected myocardial ischemia.

INTRODUCTION: Peak oxygen uptake (VO2) is prognostic for morbidity and mortality. Estimating aerobic capacity during traditional exercise stress testing is common as it has been shown that total treadmill time on the Bruce protocol predicts peak VO2. However, the potential to overestimate peak VO2 exists and may have clinical implications regarding the interpretation of exercise test data. METHODS: Subjects (N = 303) with symptoms suggestive of myocardial ischemia underwent a myocardial perfusion study and an exercise test with simultaneous ventilatory expired gas analysis. Estimated peak VO2 from the Bruce treadmill protocol was compared with measured peak VO2. The Duke Treadmill Score (DTS) was calculated with treadmill time (DTS(time)) and also with measured VO2 (DTS(measured)),expressed as metabolic equivalents (METs), and converted to time. RESULTS: Peak measured METs was significantly lower than peak estimated METs in the entire cohort (6.5 ± 1.9 vs 8.8 ± 2.8, P < .001) as well as in female (5.7 ± 1.4 and 7.8 ± 2.1, P < .001) and male (7.3 ± 2.0 and 9.7 ± 3.1, P < .001) subgroups. Calculation of the DTS with measured METs resulted in a significantly lower score compared with its calculation with treadmill time (2.7 ± 3.5 vs 5.8 ± 4.6, P < .001). Receiver operating characteristic curve analysis revealed that DTS(measured) produce a statistically significant model for diagnosing a perfusion defect in both men and women (P < .05), whereas DTS(time) was diagnostic only in men (P < .05). DISCUSSION: This study demonstrates that estimates of aerobic capacity are significantly higher than measured values and this difference may result in a significant underestimation of morbidity/mortality risk.

Usefulness of decrease in oxygen uptake efficiency slope to identify myocardial perfusion defects in men undergoing myocardial ischemic evaluation.

Cardiopulmonary exercise testing (CPX) might aid in the diagnosis of coronary artery disease. However, a heterogeneous clinical population without previous workup bias has not been studied nor has a more extensive list of CPX variables. A total of 303 subjects (age 49.9 ± 11.6 years, 157 men) with symptoms suggestive of coronary artery disease underwent CPX and a single photon emission computed tomographic myocardial perfusion study (MPS). Ventilatory efficiency was calculated using the oxygen uptake efficiency slope (OUES). The change in the OUES was calculated by subtracting the OUES response during the first 50% of CPX from the OUES obtained during the last 25% of CPX. A negative change in the OUES (< 0) from the first 50% to the last 25% of CPX was predictive of positive MPS findings only in the male subjects. The diagnostic significance of the change in OUES in men was found for any level (including equivocal studies) of positive MPS findings (area under the curve 0.67, 95% confidence interval 0.59 to 0.76, p < 0.0001) and was even stronger in those with a more definitive (excluding equivocal studies) perfusion defect (area under the curve 0.76, 95% confidence interval 0.67 to 0.85; relative risk 5.4, 95% confidence interval 2.1 to 13.8, p < 0.0001). In conclusion, this is the first time that a change in ventilatory efficiency, assessed using the OUES, has been shown to be predictive of positive MPS findings However, the OUES change only provided diagnostic information for men, a finding that warrants additional analysis.