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    Pharmacological Studies Of Alpha-1 Adrenergic Receptors

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    Bruchas_Michael-2004.pdf (2.417Mb)
    Bruchas_Michael-PhD-2004.pdf (4.702Mb)
    Author
    Bruchas, Michael Raymond
    Date
    2004-06

    Degree
    PhD (Doctor of Philosophy), Pharmacology
    Copyright: Thesis/Dissertation © Michael Raymond Bruchas, 2004

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    Abstract

    Abstract
    Recently an immortalized epithelial ceil line, SMG-C10, was isolated from rat submandibular gland cells. We compared the pharmacological characteristics of ar AR in SMG-C10 cells using [125I]BE 2254. The subtype-selective antagonists 5- methyurapidil (a-1A selective), BMY 7378 (a-1D selective), and chloroethylclonidine (CEC) (a-1e selective) were used to determine a1-AR subtype expression in the rat submandibular gland and SMG-C10 cells. Affinities (Ki’s) in SMG-C10 and for 5- methylurapidil (KiH = 0.64 nM and KiL = 91 nM ) were consistent with binding sites for the aiA-AR and the a1B-AR. CEC treatment followed by saturation binding revealed a population of a1-ARs sensitive to CEC at conditions selective for the otiB- AR Western blotting for phosphorylation of ERK 1/2 was used to determine whether the aiB-ARs in SMG-C10 couple to mitogen-activated protein kinase pathways. Using arAR subtype-selective antagonists it was determined that phenylephrine (10-100pM) stimulated ERK 1/2 phosphorylation (4-5 fold over basal) was mediated by the aiB-AR subtype. We also used the aiA-AR subtype selective antagonist A 61603 and confirmed that the a1a-AR does not activate ERK 1/2 in SMG-C10 cells. Furthermore, the aiB-AR stimulated ERK 1/2 phosphorylation was attenuated by the cholesterol inhibitors filipin and methyl-p-cyclodextrin. Prelimary experiments also demonstrated the a1-ARs in SMG-C10 cells can activate p38 but do not activate JNK. These data suggest that ai-ARs may couple to distinct signaling pathways in SMG-C10 cells and furthermore that the SMG-C10 cells may provide a useful model to study a1B-AR signaling in submandibular glands.
    URI
    http://hdl.handle.net/10504/63698
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