An elusive problem in the adhesion G protein‐coupled receptor (AGPCR) field is full understanding of the activation mechanisms of the 33‐member receptor class. With the recent solution of active‐state structures of nearly one quarter of AGPCRs, clarity has been brought to how AGPCRs are activated in response to endogenous full agonists. AGPCRs are self‐activated via a tethered peptide agonist (TA) that transitions from a concealed or encrypted location to a decrypted state that binds to a typical GPCR orthosteric binding pocket. Here, we summarize the key milestones that led to the discovery of the AGPCR TA activation mechanism and discuss how extracellular shear forces may initiate TA decryption in physiological contexts. We compare the new active‐state AGPCR structures and note that the orthosteric site‐engaged TAs adopt a remarkably similar partial α‐helical hook‐like conformation, despite divergence of overall receptor similarity. Further, we contrast the TA‐bound AGPCR structures to a partially active AGPCR structure to highlight the transitions AGPCRs may undergo during activation. Finally, we provide commentary on the validity of alternative AGPCR activation mechanisms.
Individuals use data gathering methods to inform judgments and behaviors. Effective interaction with the environment depends on these having high accuracy and low noise, but when they become abnormal, aberrant thoughts and perceptions can occur. In this study, we examined if data gathering methods were consistent across tasks that relied on different cognitive abilities, specifically visual perception and probabilistic reasoning. Thirty-four non-clinical participants engaged in the Ebbinghaus Illusion and the Jumping to Conclusions tasks, while also completing questionnaires concerning aspects of delusion formation. A significant, positive correlation was observed between performance on the Ebbinghaus Illusion and the Jumping to Conclusions tasks. Both tasks were negatively correlated with the General Conspiracy Belief Scale. The results suggest an underlying mechanism for data gathering that is consistent across behavioral domains and exists on a continuum in the general population.
Signaling via heterotrimeric G proteins is critical to maintaining cardiovascular homeostasis. Abnormal G protein signaling due to the loss of G protein regulation by proteins such as regulators of G protein signaling (RGS) proteins is implicated in several cardiovascular disorders such as hypertension, cardiac hypertrophy, and heart failure. RGS act as GTPase activating proteins (GAPs) to control the kinetics and amplitude of G protein signaling. Multiple RGS proteins are prominently expressed in the cardiovascular system; however, it is unknown whether their activities/functions are coordinated to control G protein signaling and cardiovascular function. This study used mice concurrently lacking RGS2 and 5 ( Rgs2/5 dbKO) to determine how the dual loss of potent GAPs for Gq/11 and Gi/o class G proteins affects cardiovascular function. Blood pressure and heart rate in conscious, freely moving mice were monitored via radiotelemetry. Surgical implantation of the radiotelemetry device induced marked systolic blood pressure increase in Rgs2/5 dbKO mice (WT: 140 ± 6 vs. dbKO: 170 ± 2 mmHg; p <0.01) at baseline, which gradually declined but remained elevated above wild type (WT) control level several days later. Whereas all WT mice survived the surgery, ~70-80% of male Rgs2/5 dbKO mice died 72-96 hr post-surgery. When subjected to cardiac stress test using acute dobutamine infusion and echocardiography, male Rgs2/5 dbko mice showed hypocontractile response relative to WT mice. Freshly isolated ventricular cardiomyocytes from male Rgs2/5 dbKO mice showed decreased fractional shortening (WT: 16.1 ± 4.3 vs. dbKO: 7.4 ± 1.1 %; p <0.01) but high calcium transients (WT: 117 ± 20 vs. dbKO: 198 ± 50 au; p =0.07) at baseline, and application of electrical field stimulation or the non-selective β-adrenergic receptor agonist, isoproterenol (ISO), triggered premature calcium transients, tachyarrhythmia and death of cells from Rgs2/5 dbKO mice. Interestingly, cells from mice harboring just one copy of Rgs2 ( Rgs2+/-,Rgs5-/- ) but not Rgs5 ( Rgs2-/-,Rgs5+/- ) were resistant to low-dose ISO-induced arrhythmia. These results together suggest that RGS2 and 5 coordinate their activity to control cardiomyocyte excitation-contraction coupling and normal cardiac rhythm.
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