Our major objective is to elucidate the molecular and biochemical mechanisms both in vitro and in vivo involved in binding and activation of alpha1-adrenergic receptors (ARs) and its subsequent action on the autonomic nervous system. Alpha1-adrenergic receptors are members of the G-protein-coupled receptor family of proteins that mediate the effects of the sympathetic nervous system by binding the endogenous neurotransmitters, epinephrine and norepinephrine. Signal transduction by alpha1-ARs is involved in a variety of responses such as neurotransmission, smooth muscle contraction, cardiac and other organ system homeostasis. These receptors are a therapeutic target in the current management of hypertension, benign prostatic hypertrophy and impotence. Alterations in the signaling pathways and/or receptors themselves may contribute to the pathogenesis of neurological and cardiovascular diseases. Thus, a detailed understanding of the structure-function of these receptors and their signal transduction mechanisms will be crucial to our understanding of the pathology and treatment of these diseases. Our laboratory has made considerable strides into the structure-function of alpha1-ARs subtypes (alpha1a, alpha1b, alpha1d) by characterizing determinants in the binding pocket that contribute to agonist binding and subtype selectivity. We have also through the use of constitutively active mutations provided insights into the activation mechanism. Based on these results, we now propose to address the following specific aims on structure-function analysis in vitro by concentrating on how antagonists and benzodiazepines bind and modulate alpha1-AR function and the mechanism of the poor efficacy of the alpha1d-subtype. This will enhance our understanding of the binding pocket, the signaling differences between alpha1-subtypes and may enhance new drug design. We will also explore possible pathologies from alpha1-subtype overactivity in vivo and to more clearly define the role of the alpha1a-subtype in cardiovascular function.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL061438-01A1
Application #
2908627
Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Kitt, Cheryl A
Project Start
1999-07-15
Project End
2003-06-30
Budget Start
1999-07-15
Budget End
2000-06-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Doze, Van A; Papay, Robert S; Goldenstein, Brianna L et al. (2011) Long-term ?1A-adrenergic receptor stimulation improves synaptic plasticity, cognitive function, mood, and longevity. Mol Pharmacol 80:747-58
Lentz, Margaret R; Degaonkar, Mahaveer; Mohamed, Mona A et al. (2010) Exploring the relationship of macrophage colony-stimulating factor levels on neuroaxonal metabolism and cognition during chronic human immunodeficiency virus infection. J Neurovirol 16:368-76
Perez, Dianne M; Papay, Robert S; Shi, Ting (2009) alpha1-Adrenergic receptor stimulates interleukin-6 expression and secretion through both mRNA stability and transcriptional regulation: involvement of p38 mitogen-activated protein kinase and nuclear factor-kappaB. Mol Pharmacol 76:144-52
Gupta, Manveen K; Papay, Robert S; Jurgens, Chris W D et al. (2009) alpha1-Adrenergic receptors regulate neurogenesis and gliogenesis. Mol Pharmacol 76:314-26
Perez, Dianne M (2007) Structure-function of alpha1-adrenergic receptors. Biochem Pharmacol 73:1051-62
Jane-wit, Daniel; Altuntas, Cengiz Z; Johnson, Justin M et al. (2007) Beta 1-adrenergic receptor autoantibodies mediate dilated cardiomyopathy by agonistically inducing cardiomyocyte apoptosis. Circulation 116:399-410
Duan, Zhong-Hui; Hughes, Brent; Reichel, Lothar et al. (2006) The relationship between protein sequences and their gene ontology functions. BMC Bioinformatics 7 Suppl 4:S11
Shi, Ting; Duan, Zhong-Hui; Papay, Robert et al. (2006) Novel alpha1-adrenergic receptor signaling pathways: secreted factors and interactions with the extracellular matrix. Mol Pharmacol 70:129-42
Papay, Robert; Gaivin, Robert; Jha, Archana et al. (2006) Localization of the mouse alpha1A-adrenergic receptor (AR) in the brain: alpha1AAR is expressed in neurons, GABAergic interneurons, and NG2 oligodendrocyte progenitors. J Comp Neurol 497:209-22
Perez, Dianne M; Karnik, Sadashiva S (2005) Multiple signaling states of G-protein-coupled receptors. Pharmacol Rev 57:147-61

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