Article

Alpha-1-adrenergic receptors: Targets for agonist drugs to treat heart failure

Cardiology Division, VA Medical Center, San Francisco, CA, USA.
Journal of Molecular and Cellular Cardiology (Impact Factor: 5.22). 11/2010; 51(4):518-28. DOI: 10.1016/j.yjmcc.2010.11.014
Source: PubMed

ABSTRACT Evidence from cell, animal, and human studies demonstrates that α1-adrenergic receptors mediate adaptive and protective effects in the heart. These effects may be particularly important in chronic heart failure, when catecholamine levels are elevated and β-adrenergic receptors are down-regulated and dysfunctional. This review summarizes these data and proposes that selectively activating α1-adrenergic receptors in the heart might represent a novel and effective way to treat heart failure. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure."

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Available from: Brian Jensen, Feb 18, 2015
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    • "α 1 -AR is expressed in variety of human tissue [10] and α 1 -AR stimulation has been shown to play important roles in cellular physiological functions, such as 1) regulation of smooth muscle contraction and tone in vascular system [9], prostate, urethra, bladder [11], uterine [12] and iris [13], 2) myocardial inotropy and chronotropy [14], 3) hepatic glucose metabolism [15], 4) water secretion at salivary gland [16] and 5) neurotransmission in central nerve system [9]. In addition, chronic α 1 -AR stimulation leads to pathophysiological responses in the various cells/ tissues via both cPKC and nPKC isoform signaling pathways, including cardiac hypertrophy [17] [18], hypertension and atherosclerosis [19] [20] in cardiovascular system and portal hypertension and fibrosis in liver [21]. Despite strong interest in the mechanism underlying α 1 -AR signaling-mediated pathology, especially in cardiovascular system, little is known about the molecular mechanisms for the PKC isoform-specific kinetics of activation and translocation. "
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    ABSTRACT: Protein kinase C (PKC) plays key roles in the regulation of signal transduction and cellular function in various cell types. At least ten PKC isoforms have been identified and intracellular localization and trafficking of these individual isoforms are important for regulation of enzyme activity and substrate specificity. PKC can be activated at downstream of Gq-protein coupled receptor (GqPCR) signaling and translocated to the various cellular compartments including plasma membrane (PM). Recent reports suggested that a different type of GqPCRs would activate different PKC isoforms (classic, novel and atypical PKCs) with different trafficking patterns. However, the knowledge of isoform-specific activation of PKC by each GqPCR is limited. α1-Adrenoceptor (α1-AR) is the one of the GqPCR highly expressed in the cardiovascular system. In this study, we examined the isoform-specific dynamic translocation of PKC in living HEK293T cells by α1-AR stimulation (α1-ARS). Rat PKCα, βI, βII, δ, ε and ζ fused with GFP at C-term were co-transfected with human α1A-AR into HEK293T cells. The isoform-specific dynamic translocation of PKC in living HEK293T cells by α1-ARS using phenylephrine was measured by confocal microscopy. Before stimulation, GFP-PKCs were localized at cytosolic region. α1-ARS strongly and rapidly translocated a classical PKC (cPKC), PKCα, (<30s) to PM, with PKCα returning diffusively into the cytosol within 5 min. α1-ARS rapidly translocated other cPKCs, PKCβI and PKCβII, to the PM (<30s), with sustained membrane localization. One of novel PKCs (nPKCs), PKCε, but not another nPKC, PKCδ, was translocated by α1-AR stimulation to the PM (<30s) and its membrane localization was also sustained. Finally, α1-AR stimulation did not cause a diacylglycerol-insensitive atypical PKC, PKCζ translocation. Our data suggest that PKCα, β and ε activation may underlie physiological and pathophysiological responses of α1-AR signaling for the phosphorylation of membrane-associated substrates including ion-channel and transporter proteins in the cardiovascular system. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 08/2015; DOI:10.1016/j.bbrc.2015.08.040 · 2.28 Impact Factor
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    • "The role of PIP2 modulation of native cardiac KCNQ1 channels is less well established. However, in the heart, α1 adrenergic receptors (α1 AR) activate Gq signaling pathways (Jensen et al., 2011) which has been shown in heterologous expression systems to modulate IKs channels (formed by KCNQ1 and the auxiliary subunit KCNE1) in through a combination of PIP2 hydrolysis and PKC phosphorylation (Matavel and Lopes, 2009). Furthermore, KCNQ1 channel mutations associated with cardiac arrythmias in patients have been shown to affect PIP2-dependent activation, suggesting that native IKs channels are sensitive to PIP2 binding (Park et al., 2005; Li et al., 2011; Zaydman et al., 2013). "
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    ABSTRACT: Voltage-gated potassium (Kv) channels contain voltage-sensing (VSD) and pore-gate (PGD) structural domains. During voltage-dependent gating, conformational changes in the two domains are coupled giving rise to voltage-dependent opening of the channel. In addition to membrane voltage, KCNQ (Kv7) channel opening requires the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2). Recent studies suggest that PIP2 serves as a cofactor to mediate VSD-PGD coupling in KCNQ1 channels. In this review, we put these findings in the context of the current understanding of voltage-dependent gating, lipid modulation of Kv channel activation, and PIP2-regulation of KCNQ channels. We suggest that lipid-mediated coupling of functional domains is a common mechanism among KCNQ channels that may be applicable to other Kv channels and membrane proteins.
    Frontiers in Physiology 05/2014; 5:195. DOI:10.3389/fphys.2014.00195 · 3.50 Impact Factor
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    • "Some of the earliest successes in using GPCRs as therapeutic targets are the subfamily of adrenergic receptors [3]. In fact, adrenergic agonists and antagonists constitute the largest single class of therapeutic drugs prescribed for congestive heart failure, hypertension and asthma [1,4-6]. "
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    ABSTRACT: Protein phosphorylation of G-protein-coupled receptors (GPCR) is central to the myriad of functions that these ubiquitous receptors perform in biology. Although readily addressable with the use of phospho-specific antibodies, analysis phosphorylation at the level of stoichiometry requires receptor isolation and advanced proteomics. We chose two key sites of potential phosphorylation of human beta2-adrenergic receptor (beta2AR residues S355 and S356) to ascertain the feasibility of applying targeted mass spectrometry to establishing the stoichiometry of the phosphorylation. We stimulated HEK293 cells stably expressing Flag-tagged beta2AR-eGFP with 10 muM beta-adrenergic agonist (isoproterenol) and made use of proteomics and targeted mass spectrometry (MS) to quantify the molar ration of phosphorylation on S355 and S356 versus non-phosphorylated receptor in agonist-treated cells. Phosphorylation of either S355 or S356 residue occurred only for agonist-occupied beta2AR. The results demonstrated that pS356 is the dominant site of protein phosphorylation. The abundance of the p356 was 8.6-fold more than that of pS355. Calculation of the molar ratio of phosphorylated (pS355 plus pS356) versus non-phosphorylated receptor reveals that at high occupancy of the receptor only 12.4% of the beta2AR is phosphorylated at these sites. Application of advanced proteomics and use of the most sensitive targeted MS strategy makes possible the detection and quantification of phosphorylation of very low abundance peptide digests of beta2AR. Establishing the stoichiometry of two key sites of agonist-stimulated phosphorylation with beta2AR is an essential first-step to global analysis of the stoichiometry of GPCR phosphorylation.
    Journal of Molecular Signaling 04/2014; 9(1):3. DOI:10.1186/1750-2187-9-3
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