Inability Of Receptor Research Articles

Cardiorespiratory Fitness Level Alters Blood Pressure Responses Induced By Histamine H1- And H2-receptor Blockade During Dynamic Exercise

INTRODUCTION: Epidemiological studies have reported that greater cardiorespiratory fitness (CRF) is associated with lower blood pressure (BP). Histamine receptor-mediated peripheral vasodilation contributes to post-exercise hypotension and lowing exercising BP responses. Previously, our laboratory found that overactive BP responses to exercise were induced by the inability of histamine receptors in individuals with prehypertension. However, it is still unknown that CRF can impact BP responses elicited by the inability of the receptors. PURPOSE: This study was to assess whether aerobic fitness is effective in lowering excessive BP responses induced by the blockade of histamine receptors METHODS: In twelve male and female subjects (6 high CRF and 6 low CRF), we examined the effects of histamine H1- and H2- receptor blockades on heart rate (HR), stroke volume (SV), cardiac output (CO), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and total peripheral resistance (TPR) at workloads corresponding to 40% and 60% workloads of VO2peak during cycling exercise. RESULTS: Our study indicated that compared to the high CRF group, changes in MAP from the baselines were higher in the low CRF group before the blockade at each workload (40%: D14±2 vs. 8±1 mmHg; 60%: D21±3 vs. 15±2 mmHg). The changes in MAP in response to the blockade during exercise were substantially lower in the high CRF group (40%: D18±2 vs. 11±1 mmHg; 60%: D29±3 vs. 19±2 mmHg). CONCLUSIONS: Our study suggests that an improvement in CRF likely reduces exaggerated BP responses elicited due to the inability of histamine receptors in pathological conditions such as prehypertension and hypertension.

G protein‐coupled receptor kinase 2 can enhance β‐arrestin recruitment to the D 2 dopamine receptor in the absence of receptor phosphorylation

The D2 dopamine (DA) receptor (D2R) signals through two main pathways: activation of G proteins and recruitment of β-arrestin. Upon agonist binding to the receptor, an active signaling state is formed that leads to receptor phosphorylation by one or more members of the G protein-coupled receptor kinase (GRK) family. GRK-mediated receptor phosphorylation enhances β-arrestin interactions with many GPCRs, but this mechanism remains unclear for the D2R. We recently identified a single amino acid (F189 (5.38 using Ballesteros-Weinstein numbering)) within the ligand binding site of the D2R that acts as a micro-switch for regulating D2R interactions with β-arrestin (Sanchez-Soto et al., Sci. Signal. 13(617): eaaw5885, 2020). When F189 is mutated to alanine, the D2R-F1895.38A mutant is capable of activating G proteins, but is unable to recruit β-arrestin, i.e., D2R-F1895.38A is a G protein-biased receptor. To investigate the mechanisms underlying the biased signaling of D2R-F1895.38A, its interactions with GRK2 were explored using a variety of bioluminescence resonance energy transfer (BRET) assays. Importantly, we found that D2R-F1895.38A does not recruit GRK2 upon agonist stimulation. This finding suggests that the absence of D2R-F1895.38A -GRK2 interactions may underlie the receptor's inability to recruit β-arrestin. To test this hypothesis, we examined DA-stimulated β-arrestin and GRK2 recruitment using a phosphorylation-defective D2R mutant (Namkung et. al., JBC 284:34103, 2009), the GRK2/3 inhibitor Compound 101, and cells in which expression of one or more GRK subtypes were eliminated by CRISPR-Cas9 technology. Strikingly, the phosphorylation-defective D2R mutant was not impaired in its ability to recruit either GRK2 or β-arrestin. In addition, treatment with Compound 101 resulted in a decrease, but not elimination of DA-stimulated β-arrestin recruitment to the WT D2R, suggesting that, while GRK2 kinase activity is required for enhancement of β-arrestin recruitment, phosphorylation of the D2R is not involved. We further examined the role of GRK2 by using a GRK2 KO cell line and found that, while β-arrestin recruitment to the D2R and D2R internalization were diminished, they were not eliminated. In addition, cells completely lacking all GRK subtypes (Total GRK KO) showed an even lower β-arrestin recruitment and D2R internalization suggesting that multiple GRK subtypes might facilitate D2R-β-arrestin interactions. Finally, overexpression of GRKs2, 3, 4, 5, or 6 in the Total GRK KO cells increased β-arrestin recruitment to the D2R. Taken together, these data suggest that while GRK2, and potentially other GRK subtypes, play a facilitatory role in regulating β-arrestin recruitment to the D2R, and thus can potentially mediate receptor signaling bias, receptor phosphorylation itself does not appear to be involved.

Coevolutionary feedback elevates constitutive immune defence: a protein network model.

BackgroundOrganisms have evolved a variety of defence mechanisms against natural enemies, which are typically used at the expense of other life history components. Induced defence mechanisms impose minor costs when pathogens are absent, but mounting an induced response can be time-consuming. Therefore, to ensure timely protection, organisms may partly rely on constitutive defence despite its sustained cost that renders it less economical. Existing theoretical models addressing the optimal combination of constitutive versus induced defence focus solely on host adaptation and ignore the fact that the efficacy of protection depends on genotype-specific host-parasite interactions. Here, we develop a signal-transduction network model inspired by the invertebrate innate immune system, in order to address the effect of parasite coevolution on the optimal combination of constitutive and induced defence.ResultsOur analysis reveals that coevolution of parasites with specific immune components shifts the host’s optimal allocation from induced towards constitutive immunity. This effect is dependent upon whether receptors (for detection) or effectors (for elimination) are subjected to parasite counter-evolution. A parasite population subjected to a specific immune receptor can evolve heightened genetic diversity, which makes parasite detection more difficult for the hosts. We show that this coevolutionary feedback renders the induced immune response less efficient, forcing the hosts to invest more heavily in constitutive immunity. Parasites diversify to escape elimination by a specific effector too. However, this diversification does not alter the optimal balance between constitutive and induced defence: the reliance on constitutive defence is promoted by the receptor’s inability to detect, but not the effectors’ inability to eliminate parasites. If effectors are useless, hosts simply adapt to tolerate, rather than to invest in any defence against parasites. These contrasting results indicate that evolutionary feedback between host and parasite populations is a key factor shaping the selection regime for immune networks facing antagonistic coevolution.ConclusionParasite coevolution against specific immune defence alters the prediction of the optimal use of defence, and the effect of parasite coevolution varies between different immune components.Electronic supplementary materialThe online version of this article (doi:10.1186/s12862-016-0667-3) contains supplementary material, which is available to authorized users.

Role of cyclic AMP in cardiac beta-adrenoceptor desensitization: studies using prenalterol and inhibitors of phosphodiesterase.

We examined the effects of prolonged exposure of cardiac cells in primary culture to the partial beta-adrenoceptor agonist prenalterol and inhibitors of phosphodiesterase on their subsequent ability to increase intracellular cyclic AMP during a 5-min exposure to 50 microM isoprenaline (receptor responsiveness). Although prenalterol possesses only 7% of the agonist activity of isoprenaline on adenylate cyclase, it induces extensive beta-adrenoceptor desensitization. Three hours after exposing the cells to 1 microM prenalterol, beta-adrenoceptor responsiveness was reduced by 40% (p less than 0.05), whereas after 12 h the reduction averaged 55%. Prolonging the incubation time to 48 h had no further effect on the magnitude of receptor desensitization. The magnitude of the desensitization was concentration dependent. On exposure of cells to 10(-8) M prenalterol for 16 h, receptor responsiveness was reduced by 19%, and at concentrations of 1 microM and higher responsiveness was reduced by 60% (p less than 0.01). Receptor desensitization appeared to be due to an inability of receptors to activate adenylate cyclase as well as to receptor loss. To investigate if beta-adrenoceptor desensitization as well as receptor loss could be mediated by cyclic AMP, the cells were exposed for 16 h to inhibitors of phosphodiesterase. Exposure of cells to the phosphodiesterase inhibitor isobutylmethylxanthine (0.1 mM) (which increased intracellular cyclic AMP by between 50 and 150%) also induced receptor desensitization. The reduction in receptor responsiveness averaged 62% (p less than 0.01). The loss in responsiveness could be accounted for by an inability of receptors to activate adenylate cyclase as well as by receptor loss.(ABSTRACT TRUNCATED AT 250 WORDS)