Cardiac β2 adrenergic receptor deletion drives calmodulin kinase II upregulation to induce connection tissue growth factor in cardiac fibrosis and diastolic dysfunction.

Abnormalities of Ca2+ signaling in the heart lead to common cardiac remodeling in the pathogenesis of cardiovascular disorders. The activation of calmodulin-dependent protein kinase II (CaMKII) is regulated by elevated intracellular Ca2+ level in cardiomyocytes, driving the progression of myocardial dysfunction. In this study, using models of β2 adrenergic receptor (β2AR) deficiency in cardiomyocytes (β2AR-CKO), we observed an increased phosphorylation of CaMKII and upregulation of gene expression and protein level of the fibrotic marker connective tissue growth factor (CTGF) in the myocytes.

Signaling by intracellular β-adrenergic receptors regulates AMPA receptor trafficking and synaptic plasticity.

Signaling by norepinephrine (NE) via adrenergic receptors (ARs) mediates attention, yet the underlying molecular mechanisms are largely unknown. AMPA receptors (AMPARs) form a complex with βARs, G, adenylyl cyclase, and protein kinase A (PKA) to augment AMPAR phosphorylation and, thereby, surface expression. We show that signaling by intracellular βARs is required for these effects and two different forms of long-term potentiation (LTP) that depend on βAR signaling and phosphorylation of the AMPAR GluA1 subunit on S845.

Mealtime alters daily rhythm in nuclear O-GlcNAc proteome to regulate hepatic gene expression.

The liver circadian clock and hepatic transcriptome are highly responsive to metabolic signals generated from feeding-fasting rhythm. Previous studies have identified a number of nutrient-sensitive signaling pathways that could interpret metabolic input to regulate rhythmic hepatic biology. Here, we investigated the role of O-GlcNAcylation, a nutrient-sensitive post-translational modification (PTM) in mediating metabolic regulation of rhythmic biology in the liver.

Arterial Myocyte Pannexin 1 Channel Controls Vascular Reactivity in Diabetic Hyperglycemia.

Background: Diabetic hyperglycemia promotes vasoconstriction by activating an ATP-dependent P2Y (P2Y-like receptor)/AC5 (adenylyl cyclase 5)/AKAP5 (A-kinase anchoring protein 5)/PKA (protein kinase A)/Ca1.2 (L-type voltage-dependent calcium channel 1.2) nanocomplex in arterial myocytes, but upstream mechanisms are unclear.

Habitual Exercise Modulates Neuroimmune Interaction to Mitigate Aortic Stiffness.

Background: Exercise augments hemodynamic shear to activate mechano-sensitive molecular transducers in the vascular endothelium. Recently, the central nervous system has been reported to mediate neuroimmune interactions in the aortic adventitia (AA). Whether exercise modulates sympathetic nerve interactions with the immune cells to mitigate aortic stiffness remains unknown.

Structure and dynamics determine G protein coupling specificity at a class A GPCR.

G protein-coupled receptors (GPCRs) exhibit varying degrees of selectivity for different G protein isoforms. Despite the abundant structures of GPCR-G protein complexes, little is known about the mechanism of G protein coupling specificity. The β-adrenergic receptor is an example of GPCR with high selectivity for Gαs, the stimulatory G protein for adenylyl cyclase, and much weaker for the Gαi family of G proteins inhibiting adenylyl cyclase.

Multicilia dynamically transduce Sonic Hedgehog signaling to regulate choroid plexus functions.

The choroid plexus is a major site for cerebrospinal fluid (CSF) production, characterized by a multiciliated epithelial monolayer that regulates CSF production. We demonstrate that defective choroid plexus ciliogenesis or intraflagellar transport yields neonatal hydrocephalus, at least in part due to increased water channel Aqp1 and ion transporter Atp1a2 expression. We demonstrate choroid plexus multicilia as sensory cilia, transducing both canonical and non-canonical Sonic Hedgehog (Shh) signaling.

Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G protein.

G protein-coupled receptors (GPCRs) and G proteins transmit signals from hormones and neurotransmitters across cell membranes, initiating downstream signaling and modulating cellular behavior. Using advanced computer modeling and simulation, we identified atomistic-level structural, dynamic, and energetic mechanisms of norepinephrine (NE) and stimulatory G protein (G) interactions with β-adrenergic receptors (βARs), crucial GPCRs for heart function regulation and major drug targets. Our analysis revealed distinct binding behaviors of NE within βAR and βAR despite identical orthosteric binding pockets.

Multicilia dynamically transduce Shh signaling to regulate choroid plexus functions.

Choroid plexus is a major site for cerebrospinal fluid (CSF) production, characterized by a multiciliated epithelial monolayer that regulates CSF production. We demonstrate that defective choroid plexus ciliogenesis or Intraflagellar transport yields neonatal hydrocephalus, at least in part, due to increased water channel Aqp1 and ion transporter Atp1a2 expression. We demonstrate choroid plexus multicilia as sensory cilia, transducing both canonical and non-canonical Shh signaling.

Inhibition of the upregulated phosphodiesterase 4D isoforms improves SERCA2a function in diabetic cardiomyopathy.

Background And Purpose: Sarcoplasmic reticulum Ca-ATPase (SERCA2a) is impaired in heart failure. Phosphodiesterases (PDEs) are implicated in the modulation of local cAMP signals and protein kinase A (PKA) activity essential for cardiac function. We characterise PDE isoforms that underlie decreased activities of SERCA2a and reduced cardiac contractile function in diabetic cardiomyopathy.

Carvedilol Activates a Myofilament Signaling Circuitry to Restore Cardiac Contractility in Heart Failure.

Phosphorylation of myofilament proteins critically regulates beat-to-beat cardiac contraction and is typically altered in heart failure (HF). β-Adrenergic activation induces phosphorylation in numerous substrates at the myofilament. Nevertheless, how cardiac β-adrenoceptors (βARs) signal to the myofilament in healthy and diseased hearts remains poorly understood.

Differential Downregulation of β-Adrenergic Receptor Signaling in the Heart.

Background: Chronic sympathetic stimulation drives desensitization and downregulation of β1 adrenergic receptor (βAR) in heart failure. We aim to explore the differential downregulation subcellular pools of βAR signaling in the heart.

Methods And Results: We applied chronic infusion of isoproterenol to induced cardiomyopathy in male C57BL/6J mice.

Structure and dynamics determine G protein coupling specificity at a class A GPCR.

G protein coupled receptors (GPCRs) exhibit varying degrees of selectivity for different G protein isoforms. Despite the abundant structures of GPCR-G protein complexes, little is known about the mechanism of G protein coupling specificity. The β2-adrenergic receptor is an example of GPCR with high selectivity for Gαs, the stimulatory G protein for adenylyl cyclase, and much weaker for the Gαi family of G proteins inhibiting adenylyl cyclase.

Loss of Myeloid Cell-Specific β2-Adrenergic Receptor Expression Ameliorates Cardiac Function and Remodeling after Acute Ischemia.

Myeloid cells, including neutrophils, monocytes and macrophages, accumulate quickly after ischemic injury in the heart where they play integral roles in the regulation of inflammation and repair. We previously reported that deletion of β2-adrenergic receptor (β2AR) in all cells of hematopoietic origin resulted in generalized disruption of immune cell responsiveness to injury, but with unknown impact on myeloid cells specifically. To investigate this, we crossed floxed β2AR (F/F) mice with myeloid cell-expressing Cre (LysM-Cre) mice to generate myeloid cell-specific β2AR knockout mice (LB2) and subjected them to myocardial infarction (MI).

Phosphodiesterase in heart and vessels: from physiology to diseases.

Phosphodiesterases (PDEs) are a superfamily of enzymes that hydrolyze cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Both cyclic nucleotides are critical secondary messengers in the neurohormonal regulation in the cardiovascular system. PDEs precisely control spatiotemporal subcellular distribution of cyclic nucleotides in a cell- and tissue-specific manner, playing critical roles in physiological responses to hormone stimulation in the heart and vessels.

Characterizing Adrenergic Regulation of Glucose Transporter 4-Mediated Glucose Uptake and Metabolism in the Heart.

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 β adrenoreceptor (βAR) is required to increase glucose transporter 4 (GLUT4)-mediated glucose uptake in myocytes and glucose oxidation in working hearts via activating the cardiac βAR 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 βAR blocked adrenergic stimulation of GLUT4-mediated glucose uptake in myocytes and hearts.

Silencing of circCacna1c Inhibits ISO-Induced Cardiac Hypertrophy through miR-29b-2-5p/NFATc1 Axis.

Pathological cardiac hypertrophy is one of the notable causes of heart failure. Circular RNAs (circRNAs) have been studied in association with cardiac hypertrophy; however, the mechanisms by which circRNAs regulate cardiac hypertrophy remain unclear. In this study, we identified a new circRNA, named circCacna1c, in cardiac hypertrophy.

Transfer of nuclear and ribosomal material from Sox10-lineage cells to neurons in the mouse brain.

Material transfer is an essential form of intercellular communication to exchange information and resources between cells. Material transfer between neurons and from glia to neurons has been demonstrated to support neuronal survival and activity. Understanding the extent of material transfer in the healthy nervous system is limited.

Arrestin-dependent nuclear export of phosphodiesterase 4D promotes GPCR-induced nuclear cAMP signaling required for learning and memory.

G protein-coupled receptors (GPCRs) promote the expression of immediate early genes required for learning and memory. Here, we showed that β-adrenergic receptor (βAR) stimulation induced the nuclear export of phosphodiesterase 4D5 (PDE4D5), an enzyme that degrades the second messenger cAMP, to enable memory consolidation. We demonstrated that the endocytosis of βAR phosphorylated by GPCR kinases (GRKs) mediated arrestin3-dependent nuclear export of PDE4D5, which was critical for promoting nuclear cAMP signaling and gene expression in hippocampal neurons for memory consolidation.

Elucidation of a dynamic interplay between a beta-2 adrenergic receptor, its agonist, and stimulatory G protein.

G protein-coupled receptors (GPCRs) represent the largest group of membrane receptors for transmembrane signal transduction. Ligand-induced activation of GPCRs triggers G protein activation followed by various signaling cascades. Understanding the structural and energetic determinants of ligand binding to GPCRs and GPCRs to G proteins is crucial to the design of pharmacological treatments targeting specific conformations of these proteins to precisely control their signaling properties.

Whole-heart multiparametric optical imaging reveals sex-dependent heterogeneity in cAMP signaling and repolarization kinetics.

Cyclic adenosine 3',5'-monophosphate (cAMP) is a key second messenger in cardiomyocytes responsible for transducing autonomic signals into downstream electrophysiological responses. Previous studies have shown intracellular heterogeneity and compartmentalization of cAMP signaling. However, whether cAMP signaling occurs heterogeneously throughout the intact heart and how this drives sex-dependent functional responses are unknown.

Adenylyl cyclase isoform 1 contributes to sinoatrial node automaticity via functional microdomains.

Sinoatrial node (SAN) cells are the heart's primary pacemaker. Their activity is tightly regulated by β-adrenergic receptor (β-AR) signaling. Adenylyl cyclase (AC) is a key enzyme in the β-AR pathway that catalyzes the production of cAMP.