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Whereas adrenergic stimulation promotes cardiac function that demands more fuel and energy, how this receptor controls cardiac glucose metabolism is not defined. This study shows that the cardiac β2 adrenoreceptor (β2AR) is required to increase glucose transporter 4 (GLUT4)-mediated glucose uptake in myocytes and glucose oxidation in working hearts via activating the cardiac β2AR and promotes the G inhibitory-phosphoinositide 3-kinase-protein kinase B cascade to increase phosphorylation of TBC1D4 (aka AS160), a Rab guanosine triphosphatase-activating protein, which is a key enzyme to mobilize GLUT4. Furthermore, deleting G-protein receptor kinase phosphorylation sites of β2AR blocked adrenergic stimulation of GLUT4-mediated glucose uptake in myocytes and hearts. This study defines a molecular pathway that controls cardiac GLUT4-mediated glucose uptake and metabolism under adrenergic stimulation.

We have recently identified a pool of intracellular β1 adrenergic receptors (β1ARs) at the sarcoplasmic reticulum (SR) crucial for cardiac function. Here, we aim to characterize the integrative control of intracellular catecholamine for subcellular β1AR signaling and cardiac function. Using anchored Förster resonance energy transfer (FRET) biosensors and transgenic mice, we determined the regulation of compartmentalized β1AR-PKA signaling at the SR and plasma membrane (PM) microdomains by organic cation transporter 3 (OCT3) and monoamine oxidase A (MAO-A), two critical modulators of catecholamine uptake and homeostasis. Additionally, we examined local PKA substrate phosphorylation and excitation-contraction coupling in cardiomyocyte. Cardiac-specific deletion of MAO-A (MAO-A-CKO) elevates catecholamines and cAMP levels in the myocardium, baseline cardiac function, and adrenergic responses. Both MAO-A deletion and inhibitor (MAOi) selectively enhance the local β1AR-PKA activity at the SR but not PM, and augment phosphorylation of phospholamban, Ca2+ cycling, and myocyte contractile response. Overexpression of MAO-A suppresses the SR-β1AR-PKA activity and PKA phosphorylation. However, deletion or inhibition of OCT3 by corticosterone prevents the effects induced by MAOi and MAO-A deletion in cardiomyocytes. Deletion or inhibition of OCT3 also negates the effects of MAOi and MAO-A deficiency in cardiac function and adrenergic responses in vivo. Our data show that MAO-A and OCT3 act in concert to fine-tune the intracellular SR-β1AR-PKA signaling and cardiac fight-or-flight response. We reveal a drug contraindication between anti-inflammatory corticosterone and anti-depressant MAOi in modulating adrenergic regulation in the heart, providing novel perspectives of these drugs with cardiac implications.

Spatiotemporal regulation of subcellular protein kinase A (PKA) activity for precise substrate phosphorylation is essential for cellular responses to hormonal stimulation. Ryanodine receptor 2 (RyR2) and (sarco)endoplasmic reticulum calcium ATPase 2a (SERCA2a) represent two critical targets of β adrenoceptor (βAR) signaling on the sarcoplasmic reticulum membrane for cardiac excitation and contraction coupling. Using novel biosensors, we show that cardiac β1AR signals to both RyR2 and SERCA2a nanodomains in cardiomyocytes from mice, rats, and rabbits, whereas the β2AR signaling is restricted from these nanodomains. Phosphodiesterase 4 (PDE4) and PDE3 control the baseline PKA activity and prevent β2AR signaling from reaching the RyR2 and SERCA2a nanodomains. Moreover, blocking inhibitory G protein allows β2AR signaling to the RyR2 but not the SERCA2a nanodomains. This study provides evidence for the differential roles of inhibitory G protein and PDEs in controlling the adrenergic subtype signaling at the RyR2 and SERCA2a nanodomains in cardiomyocytes. Video abstract.

Rationaleβ1ARs (β1-adrenoceptors) exist at intracellular membranes and OCT3 (organic cation transporter 3) mediates norepinephrine entry into cardiomyocytes. However, the functional role of intracellular β1AR in cardiac contractility remains to be elucidated.ObjectiveTest localization and function of intracellular β1AR on cardiac contractility.Methods and resultsMembrane fractionation, super-resolution imaging, proximity ligation, coimmunoprecipitation, and single-molecule pull-down demonstrated a pool of β1ARs in mouse hearts that were associated with sarco/endoplasmic reticulum Ca2+-ATPase at the sarcoplasmic reticulum (SR). Local PKA (protein kinase A) activation was measured using a PKA biosensor targeted at either the plasma membrane (PM) or SR. Compared with wild-type, myocytes lacking OCT3 (OCT3-KO [OCT3 knockout]) responded identically to the membrane-permeant βAR agonist isoproterenol in PKA activation at both PM and SR. The same was true at the PM for membrane-impermeant norepinephrine, but the SR response to norepinephrine was suppressed in OCT3-KO myocytes. This differential effect was recapitulated in phosphorylation of the SR-pump regulator phospholamban. Similarly, OCT3-KO selectively suppressed calcium transients and contraction responses to norepinephrine but not isoproterenol. Furthermore, sotalol, a membrane-impermeant βAR-blocker, suppressed isoproterenol-induced PKA activation at the PM but permitted PKA activation at the SR, phospholamban phosphorylation, and contractility. Moreover, pretreatment with sotalol in OCT3-KO myocytes prevented norepinephrine-induced PKA activation at both PM and the SR and contractility.ConclusionsFunctional β1ARs exists at the SR and is critical for PKA-mediated phosphorylation of phospholamban and cardiac contractility upon catecholamine stimulation. Activation of these intracellular β1ARs requires catecholamine transport via OCT3.

This paper is concerned with the set-membership filtering problem for the two-dimensional shift-varying systems subject to the stochastic communication protocol and uniform quantization effects. To prevent the data transmission from collisions, only one sensor can transmit the measured information to the filter at each sampling shift instant, and the selected sensor is determined by the scheduling strategy of the stochastic communication protocol. On the contrary, the uniform quantization mechanism has been employed to mitigate the influence of quantization error on filtering performance. Incorporating the stochastic communication protocol and uniform quantization mechanism, this paper proposes a set-membership filter design framework for the two-dimensional shift-varying systems with unknown-but-bounded noises. Sufficient conditions are derived for the existence of desired set-membership filter by utilizing double mathematical induction, such that the estimation error resides within the ellipsoidal set. Moreover, the optimal filtering algorithm is given by minimizing the ellipsoidal constraints. Finally, several examples are provided to illustrate the effectiveness of the proposed filter design algorithm. [ABSTRACT FROM AUTHOR]

In order to solve the difficulty that complex power quality disturbances (PQDs) are difficult to recognize accurately and efficiently under the new power system background, this paper proposes a novel PQDs recognition method based on markov transition field (MTF) and improved densely connected network (DenseNet). Firstly, the one-dimensional PQDs signal is mapped into the two- dimensional image with clear texture features by using MTF encoding method. Then, a DenseNet-S lightweight network is designed and the convolutional attention module (CBAM) is introduced to improve its feature extraction ability, so as to enhance the performance of the network. Finally, the images are input into the improved model for training and learning, and PQDs recognition is realized through the optimal model. In order to verify the effectiveness of the proposed method, experimental tests are carried out based on IEEE 1159 standard simulation dataset and real-world field measured signals dataset, and compared with existing recognition methods. The results show that the proposed method can effectively improve the recognition accuracy and noise robustness of complex PQDs, and has more advantages in disturbances recognition efficiency. It can meet the recognition accuracy and efficiency requirements of massive and complex PQDs events in engineering applications. [ABSTRACT FROM AUTHOR]

The recursive filtering problem for a class of time-varying systems with mixed time-delays subject to stochastic communication protocol and dynamic quantization effects is discussed in this article. It is assumed that only one sensor can transmit the measured information to the filter at each sampling period, and the selected sensor is determined by the scheduling strategy of the stochastic communication protocol. Based on this assumption, the dynamic upper bound of the filtering error covariance is derived for time-varying systems with mixed time-delays and an underlying scheduling protocol by solving two Riccati difference equations in each sampling period. Then, the trace of the upper bound is minimized to obtain the filter gain with the desired filtering performance. Subsequently, the boundedness issue of the filtering error covariance is investigated. Sufficient conditions are given to ensure that the filtering error covariance is exponentially bounded in the mean square. Finally, numerical examples are given to demonstrate the effectiveness and superiority of the proposed algorithm. [ABSTRACT FROM AUTHOR]