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Alpha-1D Adrenergic Receptor

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Robert M. Graham – 1st expert on this subject based on the ideXlab platform

  • The alpha(1D)-Adrenergic Receptor: cinderella or ugly stepsister.
    Molecular pharmacology, 2006
    Co-Authors: Angela M Finch, Robert M. Graham

    Abstract:

    This Perspective focuses on the alpha(1D)-Adrenergic Receptor (AR), the often neglected sibling of the alpha(1)-AR family. This neglect is due in part to its poor cell-surface expression. However, it has recently been shown that dimerization of the alpha(1D)-AR with either the alpha(1B)-AR or the beta(2)-AR increases alpha(1D)-AR cell-surface expression, and in this issue of Molecular Pharmacology, Hague et al. (p. 45) demonstrate that dimerization of the alpha(1D)-AR with the alpha(1B)-AR not only leads to increased cell-surface expression but also results in the formation of a novel functional entity.

  • Synthesis and biological evaluation of bicyclic and tricyclic substituted nortropane derivatives: discovery of a novel selective α1D-Adrenergic Receptor ligand
    Bioorganic & Medicinal Chemistry, 2004
    Co-Authors: Susan J. Mcginty, Angela M Finch, Robert M. Graham, Renate Griffith, John B. Bremner

    Abstract:

    Abstract A range of 3,6,6-trisubstituted nortropane derivatives based upon 6 β -phenyltropane-3 β ,6 α -diol have been synthesised from 6 β -hydroxytropinone, including some novel related tricyclic hemi-ketal and tricyclic ketal compounds. Derivatives were assessed for pharmacological affinity and selectivity at α 1 –Adrenergic Receptors, and 6 β -phenyl-8-azabicyclo[3.2.1]octan-3-spiro-2′-(1′,3′-dioxolane)-6-ol, a novel lead compound selective for the alpha 1D –Adrenergic Receptor, is reported.

  • Coupling of expressed alpha 1B- and alpha 1D-Adrenergic Receptor to multiple signaling pathways is both G protein and cell type specific.
    Molecular Pharmacology, 1993
    Co-Authors: Dianne M Perez, Mary Beth Deyoung, Robert M. Graham

    Abstract:

    alpha 1-Adrenergic Receptors (ARs) are members of the G protein-coupled Receptor superfamily. alpha 1-AR subtypes mediate the effects of the sympathetic nervous system, especially those involved in cardiac homeostasis. To investigate signal transduction by a novel subtype (alpha 1D), which we recently cloned, and to compare it with that by the previously characterized alpha 1B-AR, we assessed the ability of each subtype to activate polyphosphoinositide (PI) metabolism, cAMP accumulation, and arachidonic acid release in Chinese hamster ovary (CHO) and COS-1 cells expressing these subtypes after stable or transient transfection, respectively. In COS-1 and CHO cells, both the alpha 1D- and alpha 1B-AR were found to couple to PI hydrolysis through a pertussis toxin-insensitive G protein. Both alpha 1-AR subtypes also increased intracellular cAMP by an indirect mechanism, although this effect was observed only in COS-1 cells and not in CHO cells. Interestingly, alpha 1-AR-stimulated arachidonic acid release was also demonstrated for both subtypes in COS-1 cells. This release was mediated through phospholipase A2 activation and involved a pertussis toxin-sensitive G protein. alpha 1-AR-stimulated arachidonic acid release was dependent upon extracellular calcium and was inhibited by 1 microM nifedipine. Inhibitors of protein kinase C, phospholipase C, and diacylglycerol lipase did not alter alpha 1-AR-stimulated release of arachidonic acid. These findings indicate that in COS-1 cells alpha 1-AR-stimulated arachidonic acid release is most likely coupled to dihydropyridine-sensitive L-type calcium channels via a pertussis toxin-sensitive G protein. The influx of extracellular calcium then stimulates phospholipase A2 to release arachidonic acid. alpha 1-AR-stimulated arachidonic acid release could also be demonstrated in CHO cells and was pertussis toxin sensitive but nifedipine insensitive. These cells were also unresponsive to Bay K8644, indicating a lack of voltage-sensitive calcium channels in CHO cells. Nevertheless, alpha 1-AR activation increased intracellular Ca2+ levels, as assessed by fura-2 fluorescence studies. Neomycin blocked both alpha 1-AR-stimulated PI hydrolysis and increases in intracellular Ca2+ levels but did not inhibit the increase in arachidonic acid release. Taken together, these data indicate that in CHO cells alpha 1-ARs can couple directly to phospholipase A2 activation via a pertussis toxin-sensitive pathway. Thus, in these model systems we demonstrate for the first time that a single alpha 1-AR subtype can activate multiple distinct signal transduction pathways, in which Receptor-effector coupling is modulated by distinct G proteins.

Rb Moreland – 2nd expert on this subject based on the ideXlab platform

  • Cyclic AMP regulates mRNA expression of Alpha-1D and alpha-2a Adrenergic Receptors in cultured human corpus cavernosum smooth muscle cells
    International Journal of Impotence Research, 2000
    Co-Authors: A Traish, Y-h Huang, I Goldstein, Rb Moreland

    Abstract:

    While the physiological effects of contractile (e.g. norepinephrine) and relaxatory (e.g. PGE1, forskolin) agents on corpus cavernosum smooth muscle tone have been characterized, the regulation of alpha Adrenergic Receptor mRNA expression in erectile tissue remains to be investigated. The goal of this study was to investigate the modulation of alpha-1 and alpha-2 Adrenergic Receptor mRNA expression in cultured human corpus cavernosum smooth muscle cells in response to increased intracellular cAMP induced by prostaglandin E1 and forskolin. Human corpus cavernosum smooth muscle cells were incubated for 24 h with or without PGE1 (5.7 μM), forskolin (10 μM) or an admixture of both. Total RNA was prepared from the cultures. Expression of Alpha-1D Adrenergic Receptor, alpha-2a Adrenergic Receptor and m2 muscarinic acetylcholine Receptor was determined by RNase protection assays. Loading was normalized by RNase protection of the housekeeping gene, cyclophilin A. The relative abundance of mRNAs was quantitated by scanning densitometry. Treatment of human corpus cavernosum smooth muscle cells with PGE1 or forskolin resulted in decreased mRNA expression of Alpha-1D and alpha-2a Adrenergic Receptors and m2 muscarinic acetylcholine Receptor when compared to untreated cells. Combinations of PGE1 and forskolin produced a more pronounced decrease in mRNA than either agent alone. PGE1 and forskolin increased intracellular levels of cAMP in human corpus cavernosum smooth muscle cells and combinations of both agents produced a more pronounced increase in cAMP synthesis. These results suggest that cAMP modulates the expression of alpha Adrenergic Receptors, one of the principal contractile Receptor systems in the corpora cavernosa. These observations further support the concept that erectile function is a balance between contractile and relaxatory processes, which in turn regulate structure and function of the corpora cavernosa.

Moreland – 3rd expert on this subject based on the ideXlab platform

  • Cyclic AMP regulates mRNA expression of Alpha-1D and alpha-2a Adrenergic Receptors in cultured human corpus cavernosum smooth muscle cells.
    International journal of impotence research, 2000
    Co-Authors: Traish, Huang, Goldstein, Moreland

    Abstract:

    While the physiological effects of contractile (e.g. norepinephrine) and relaxatory (e.g. PGE1, forskolin) agents on corpus cavernosum smooth muscle tone have been characterized, the regulation of alpha Adrenergic Receptor mRNA expression in erectile tissue remains to be investigated. The goal of this study was to investigate the modulation of alpha-1 and alpha-2 Adrenergic Receptor mRNA expression in cultured human corpus cavernosum smooth muscle cells in response to increased intracellular cAMP induced by prostaglandin E1 and forskolin. Human corpus cavernosum smooth muscle cells were incubated for 24 h with or without PGE1 (5.7 µM), forskolin (10 µM) or an admixture of both. Total RNA was prepared from the cultures. Expression of Alpha-1D Adrenergic Receptor, alpha-2a Adrenergic Receptor and m2 muscarinic acetylcholine Receptor was determined by RNase protection assays. Loading was normalized by RNase protection of the housekeeping gene, cyclophilin A. The relative abundance of mRNAs was quantitated by scanning densitometry. Treatment of human corpus cavernosum smooth muscle cells with PGE1 or forskolin resulted in decreased mRNA expression of Alpha-1D and alpha-2a Adrenergic Receptors and m2 muscarinic acetylcholine Receptor when compared to untreated cells. Combinations of PGE1 and forskolin produced a more pronounced decrease in mRNA than either agent alone. PGE1 and forskolin increased intracellular levels of cAMP in human corpus cavernosum smooth muscle cells and combinations of both agents produced a more pronounced increase in cAMP synthesis. These results suggest that cAMP modulates the expression of alpha Adrenergic Receptors, one of the principal contractile Receptor systems in the corpora cavernosa. These observations further support the concept that erectile function is a balance between contractile and relaxatory processes, which in turn regulate structure and function of the corpora cavernosa. International Journal of Impotence Research (2000) 12, Suppl 1, S41-S47