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Journal of Cardiovascular Pharmacology Sep 2022Adrenergic receptors are critical regulators of cardiac function with profound effects on cardiac output during sympathetic stimulation. Chronic stimulation of the...
Adrenergic receptors are critical regulators of cardiac function with profound effects on cardiac output during sympathetic stimulation. Chronic stimulation of the adrenergic system of the heart under conditions of cardiac stress leads to cardiac dysfunction, hypertrophy, and ultimately failure. Emerging data have revealed that G protein-coupled receptors in intracellular compartments are functionally active and regulate distinct cellular processes from those at the cell surface. β2 adrenergic receptors internalize onto endosomes in various cell types where they have recently been shown to continue to stimulate cAMP production to selectively regulate gene expression. Other studies have identified β1 adrenergic receptors at the nuclear envelope and the Golgi apparatus. Here, we discuss data on signaling by β1 and β2 adrenergic receptors in the heart and the possible influence of their subcellular locations on their divergent physiological functions in cardiac myocytes and in cardiac pathology. Understanding the relative roles of these receptors at these locations could have a significant impact on pharmacological targeting of these receptors for the treatment of heart failure and cardiac diseases.
Topics: Heart Failure; Humans; Myocytes, Cardiac; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2; Signal Transduction
PubMed: 35881897
DOI: 10.1097/FJC.0000000000001324 -
Sympathetic activity regulates epithelial proliferation and wound healing via adrenergic receptor α.Scientific Reports Oct 2023Innervation of the intestinal mucosa by the sympathetic nervous system is well described but the effects of adrenergic receptor stimulation on the intestinal epithelium...
Innervation of the intestinal mucosa by the sympathetic nervous system is well described but the effects of adrenergic receptor stimulation on the intestinal epithelium remain equivocal. We therefore investigated the effect of sympathetic neuronal activation on intestinal cells in mouse models and organoid cultures, to identify the molecular routes involved. Using publicly available single-cell RNA sequencing datasets we show that the α isoform is the most abundant adrenergic receptor in small intestinal epithelial cells. Stimulation of this receptor with norepinephrine or a synthetic specific α receptor agonist promotes epithelial proliferation and stem cell function, while reducing differentiation in vivo and in intestinal organoids. In an anastomotic healing mouse model, adrenergic receptor α stimulation resulted in improved anastomotic healing, while surgical sympathectomy augmented anastomotic leak. Furthermore, stimulation of this receptor led to profound changes in the microbial composition, likely because of altered epithelial antimicrobial peptide secretion. Thus, we established that adrenergic receptor α is the molecular delegate of intestinal epithelial sympathetic activity controlling epithelial proliferation, differentiation, and host defense. Therefore, this receptor could serve as a newly identified molecular target to improve mucosal healing in intestinal inflammation and wounding.
Topics: Animals; Mice; Cell Proliferation; Epithelial Cells; Intestinal Mucosa; Intestines; Receptors, Adrenergic; Receptors, Adrenergic, alpha-2; Wound Healing
PubMed: 37863979
DOI: 10.1038/s41598-023-45160-w -
Trends in Endocrinology and Metabolism:... Jun 2017Recent advances show that insulin may affect β adrenergic receptor (βAR) signaling in the heart to modulate cardiac function in clinically relevant states, such as... (Review)
Review
Recent advances show that insulin may affect β adrenergic receptor (βAR) signaling in the heart to modulate cardiac function in clinically relevant states, such as diabetes mellitus (DM) and heart failure (HF). Conversely, activation of βAR regulates cardiac glucose uptake and promotes insulin resistance (IR) in HF. Here, we discuss the recent characterization of the interaction between the cardiac insulin receptor (InsR) and βAR in the myocardium, in which insulin stimulation crosstalks with cardiac βAR via InsR substrate (IRS)-dependent and G-protein receptor kinase 2 (GRK2)-mediated phosphorylation of βAR. The insulin-induced phosphorylation promotes βAR coupling to G and expression of phosphodiesterase 4D, which both inhibit cardiac adrenergic signaling and compromise cardiac contractile function. These recent developments could support new approaches for the effective prevention or treatment of obesity- or DM-related HF.
Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Humans; Insulin; Receptors, Adrenergic, beta; Receptors, Adrenergic, beta-2; Signal Transduction
PubMed: 28256297
DOI: 10.1016/j.tem.2017.02.002 -
Nature Communications Apr 2023Advances in structural biology have provided important mechanistic insights into signaling by the transmembrane core of G-protein coupled receptors (GPCRs); however,...
Advances in structural biology have provided important mechanistic insights into signaling by the transmembrane core of G-protein coupled receptors (GPCRs); however, much less is known about intrinsically disordered regions such as the carboxyl terminus (CT), which is highly flexible and not visible in GPCR structures. The β adrenergic receptor's (βAR) 71 amino acid CT is a substrate for GPCR kinases and binds β-arrestins to regulate signaling. Here we show that the βAR CT directly inhibits basal and agonist-stimulated signaling in cell lines lacking β-arrestins. Combining single-molecule fluorescence resonance energy transfer (FRET), NMR spectroscopy, and molecular dynamics simulations, we reveal that the negatively charged βAR-CT serves as an autoinhibitory factor via interacting with the positively charged cytoplasmic surface of the receptor to limit access to G-proteins. The stability of this interaction is influenced by agonists and allosteric modulators, emphasizing that the CT plays important role in allosterically regulating GPCR activation.
Topics: Signal Transduction; beta-Arrestins; Cell Line; Receptors, G-Protein-Coupled; Receptors, Adrenergic; Receptors, Adrenergic, beta-2
PubMed: 37037825
DOI: 10.1038/s41467-023-37233-1 -
Cells Dec 2020The third isotype of beta-adrenoreceptors (β3-AR) has recently come (back) into focus after the observation of its expression in white and beige human adipocytes and... (Review)
Review
The third isotype of beta-adrenoreceptors (β3-AR) has recently come (back) into focus after the observation of its expression in white and beige human adipocytes and its implication in metabolic regulation. This coincides with the recent development and marketing of agonists at the human receptor with superior specificity. Twenty years ago, however, we and others described the expression of β3-AR in human myocardium and its regulation of contractility and cardiac remodeling. Subsequent work from many laboratories has since expanded the characterization of β3-AR involvement in many aspects of cardiovascular physio(patho)logy, justifying the present effort to update current paradigms under the light of the most recent evidence.
Topics: Adipocytes, Beige; Animals; Antioxidants; Cardiovascular Diseases; Cardiovascular System; Catecholamines; Gene Expression Profiling; Gene Expression Regulation; Heart Failure; Humans; Myocardium; Protein Isoforms; Receptors, Adrenergic, beta-3; Signal Transduction
PubMed: 33276630
DOI: 10.3390/cells9122584 -
The Journal of Comparative Neurology Jun 2021Adrenergic receptors are mediators of adrenergic and noradrenergic modulation throughout the brain. Previous studies have provided evidence for the expression of...
Adrenergic receptors are mediators of adrenergic and noradrenergic modulation throughout the brain. Previous studies have provided evidence for the expression of adrenergic receptors in the midbrain auditory nucleus, the inferior colliculus (IC), but have not examined the cellular patterns of expression in detail. Here, we utilize multichannel fluorescent in situ hybridization to detect the expression of adrenergic receptor-encoding mRNA in the inferior colliculus of male and female mice. We found expression of α , α , and β receptor-encoding mRNA throughout all areas of the IC. While we observed similar levels of expression of α receptor-encoding mRNA across the subregions of the IC, α and β receptor-encoding mRNA was expressed differentially. To account for developmental changes in noradrenergic receptor expression, we measured expression levels in mice aged P15, P20, and P60. We observed little change in levels of expression across these ages. To ascertain the modulatory potential of multiple adrenergic receptor subtypes in a single IC cell, we measured co-expression of α , α , and β receptor-encoding mRNA. We found greater proportions of cells in the IC that expressed no adrenergic receptor-encoding mRNA, α1 and α2A adrenergic receptor-encoding mRNA, and α1, α2A, and β2 receptor-encoding mRNA than would be predicted by independent expression of each receptor subtype. These data suggest a coordinated pattern of adrenergic receptor expression in the IC and provide the first evidence for adrenergic receptor expression and co-expression in the subregions of the mouse auditory midbrain.
Topics: Animals; Female; Inferior Colliculi; Male; Mice; RNA, Messenger; Receptors, Adrenergic
PubMed: 33067825
DOI: 10.1002/cne.25053 -
Circulation Research Nov 2018The actions and regulation of cardiomyocyte βARs differ in several respects from the properties described for the prototypical βAR subtype; a mechanism to explain the... (Review)
Review
The actions and regulation of cardiomyocyte βARs differ in several respects from the properties described for the prototypical βAR subtype; a mechanism to explain the unique properties of the βAR subtype has never been obvious. This viewpoint summarizes recent studies that identify a novel signaling paradigm for the βAR, implicating the N-terminus as a molecular determinant of βAR responsiveness.
Topics: Adrenergic beta-Antagonists; Animals; Heart Diseases; Humans; Myocytes, Cardiac; Receptors, Adrenergic, beta
PubMed: 30571467
DOI: 10.1161/CIRCRESAHA.118.313884 -
Molecules and Cells 2015The beta2-adrenergic receptor (β2AR) family, which is the largest family of cell surface receptors in humans. Extra attention has been focused on the human GPCRs... (Comparative Study)
Comparative Study Review
The beta2-adrenergic receptor (β2AR) family, which is the largest family of cell surface receptors in humans. Extra attention has been focused on the human GPCRs because they have been studied as important protein targets for pharmaceutical drug development. In fact, approximately 40% of marketed drugs directly work on GPCRs. GPCRs respond to various extracellular stimuli, such as sensory signals, neurotransmitters, chemokines, and hormones, to induce structural changes at the cytoplasmic surface, activating downstream signaling pathways, primarily through interactions with heterotrimeric G proteins or through G-protein independent pathways, such as arrestin. Most GPCRs, except for rhodhopsin, which contains covalently linked 11 cis-retinal, bind to diffusible ligands, having various conformational states between inactive and active structures. The first human GPCR structure was determined using an inverse agonist bound β2AR in 2007 and since then, more than 20 distinct GPCR structures have been solved. However, most GPCR structures were solved as inactive forms, and an agonist bound fully active structure is still hard to obtain. In a structural point of view, β2AR is relatively well studied since its fully active structure as a complex with G protein as well as several inactive structures are available. The structural comparison of inactive and active states gives an important clue in understanding the activation mechanism of β2AR. In this review, structural features of inactive and active states of β2AR, the interaction of β2AR with heterotrimeric G protein, and the comparison with β1AR will be discussed.
Topics: Adrenergic beta-2 Receptor Agonists; Benzoxazines; Binding Sites; Crystallography, X-Ray; Heterotrimeric GTP-Binding Proteins; Humans; Models, Molecular; Propanolamines; Protein Structure, Secondary; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2
PubMed: 25537861
DOI: 10.14348/molcells.2015.2301 -
Proceedings of the National Academy of... Jun 2021A key question in receptor signaling is how specificity is realized, particularly when different receptors trigger the same biochemical pathway(s). A notable case is the...
A key question in receptor signaling is how specificity is realized, particularly when different receptors trigger the same biochemical pathway(s). A notable case is the two β-adrenergic receptor (β-AR) subtypes, β and β, in cardiomyocytes. They are both coupled to stimulatory G proteins, mediate an increase in cyclic adenosine monophosphate (cAMP), and stimulate cardiac contractility; however, other effects, such as changes in gene transcription leading to cardiac hypertrophy, are prominent only for β-AR but not for β-AR. Here, we employ highly sensitive fluorescence spectroscopy approaches, in combination with a fluorescent β-AR antagonist, to determine the presence and dynamics of the endogenous receptors on the outer plasma membrane as well as on the T-tubular network of intact adult cardiomyocytes. These techniques allow us to visualize that the β-AR is confined to and diffuses within the T-tubular network, as opposed to the β-AR, which is found to diffuse both on the outer plasma membrane as well as on the T-tubules. Upon overexpression of the β-AR, this compartmentalization is lost, and the receptors are also seen on the cell surface. Such receptor segregation depends on the development of the T-tubular network in adult cardiomyocytes since both the cardiomyoblast cell line H9c2 and the cardiomyocyte-differentiated human-induced pluripotent stem cells express the β-AR on the outer plasma membrane. These data support the notion that specific cell surface targeting of receptor subtypes can be the basis for distinct signaling and functional effects.
Topics: Animals; Cell Line; Cell Membrane; Humans; Induced Pluripotent Stem Cells; Mice; Mice, Transgenic; Molecular Imaging; Myocytes, Cardiac; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2
PubMed: 34088840
DOI: 10.1073/pnas.2101119118 -
International Journal of Molecular... Nov 2023The function of the α-adrenergic receptor phosphorylation sites previously detected by mass spectrometry was evaluated by employing mutants, substituting them with...
The function of the α-adrenergic receptor phosphorylation sites previously detected by mass spectrometry was evaluated by employing mutants, substituting them with non-phosphorylatable amino acids. Substitution of the intracellular loop 3 (IL3) sites did not alter baseline or stimulated receptor phosphorylation, whereas substitution of phosphorylation sites in the carboxyl terminus (Ctail) or both domains (IL3/Ctail) markedly decreased receptor phosphorylation. Cells expressing the IL3 or Ctail receptor mutants exhibited a noradrenaline-induced calcium-maximal response similar to those expressing the wild-type receptor, and a shift to the left in the concentration-response curve to noradrenaline was also noticed. Cells expressing the IL3/Ctail mutant exhibited higher apparent potency and increased maximal response to noradrenaline than those expressing the wild-type receptor. Phorbol ester-induced desensitization of the calcium response to noradrenaline was reduced in cells expressing the IL3 mutant and abolished in cells in which the Ctail or the IL3/Ctail were modified. In contrast, desensitization in response to preincubation with noradrenaline was unaffected in cells expressing the distinct receptor mutants. Noradrenaline-induced ERK phosphorylation was surprisingly increased in cells expressing IL3-modified receptors but not in those expressing receptors with the Ctail or IL3/Ctail substitutions. Our data indicate that phosphorylation sites in the IL3 and Ctail domains mediate and regulate α-adrenergic receptor function. Phorbol ester-induced desensitization seems to be closely associated with receptor phosphorylation, whereas noradrenaline-induced desensitization likely involves other elements.
Topics: Phosphorylation; Calcium; Norepinephrine; Phorbol Esters; Receptors, Adrenergic
PubMed: 38069285
DOI: 10.3390/ijms242316963