Adrenoceptor Pharmacology: Urogenital Applications

Ruffolo, R R; Hieble, J. Paul

doi:10.1159/000052313

Cited by 36 publications

(17 citation statements)

References 35 publications

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“…Phenoxybenzamine is known to irreversibly bind to ␣-adrenergic, H 1 -histamine, and muscarinic acetylcholine (mACh) receptors (Timmermans et al, 1985;Eglen et al, 1994;Amobi and Smith, 1995;Giardinà et al, 1995Giardinà et al, , 2002Van der Graaf and Danhof, 1997;Ruffolo and Hieble, 1999;Van der Graaf and Stam, 1999;Frang et al, 2001). Benextramine has been known to irreversibly bind to ␣ 2 -adrenoceptors (Melchiorre, 1981;Belleau et al, 1982b;Lew and Angus, 1984;Hieble et al, 1985;Timmermans et al, 1985;Taouis et al, 1987;McKernan et al, 1988;Brink et al, 2000;Umland et al, 2001), 5-HT 1A -serotonergic receptors (Stanton and Beer, 1997), H 2 -histaminergic receptors (Belleau et al, 1982a), and neuropeptide Y receptors (Melchiorre et al, 1994).…”

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Phenoxybenzamine and Benextramine, but Not 4-Diphenylacetoxy-N-[2-chloroethyl]piperidine Hydrochloride, Display Irreversible Noncompetitive Antagonism at G Protein-Coupled Receptors

Bodenstein¹,

Venter²,

Brink³

2005

The Journal of Pharmacology and Experimental Therapeutics

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Many irreversible antagonists have been shown to inactivate G protein-coupled receptors (GPCRs) and used to study agonists and spare receptors. Presumably, they bind to primary (agonist) binding sites on the GPCR, although noncompetitive mechanisms of antagonism have been demonstrated but not thoroughly investigated. We studied noncompetitive antagonism by phenoxybenzamine and benextramine at ␣ 2A -adrenoceptors in stably transfected Chinese hamster ovary cells, benextramine and 4-diphenylacetoxy-N-[2-chloroethyl]piperidine hydrochloride (4-DAMP mustard) at endogenous muscarinic acetylcholine (mACh) receptors in human neuroblastoma SH-SY5Y cells, and benextramine at serotonin 5-HT 2A

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confidence: 99%

Phenoxybenzamine and Benextramine, but Not 4-Diphenylacetoxy-N-[2-chloroethyl]piperidine Hydrochloride, Display Irreversible Noncompetitive Antagonism at G Protein-Coupled Receptors

Bodenstein¹,

Venter²,

Brink³

2005

The Journal of Pharmacology and Experimental Therapeutics

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“…Cellular signaling pathways regulated by ␣ 2A -AR in native cells include inhibition of adenylyl cyclase, activation of receptor-operated K ϩ channels, inhibition of voltage-gated Ca 2ϩ channels, and activation of the mitogen-activated protein kinase cascade (1)(2)(3). Many cells that express ␣ 2 -ARs are polarized, including renal and intestinal epithelia, where the ␣ 2 -AR serves to regulate sodium and water resorption (4,5), as well as neurons, where these receptors act to suppress neurotransmitter release (6). The physiological functions mediated by ␣ 2 -ARs in polarized cells are dependent upon precise localization of the receptor at the basolateral surface to gain access to neurally delivered and blood-delivered catecholamines.…”

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confidence: 99%

Spinophilin Stabilizes Cell Surface Expression of α2B-Adrenergic Receptors

Brady

Wang

Colbran

et al. 2003

Journal of Biological Chemistry

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␣ 2 -Adrenergic receptors (ARs) 1 are members of the large superfamily of G protein-coupled receptors that contain seven putative transmembrane spanning regions. There are three ␣ 2 -AR subtypes (␣ 2A , ␣ 2B , and ␣ 2C ), each of which is activated by the endogenous catecholamines, epinephrine and norepinephrine, and performs multiple physiological functions via pertussis toxin-sensitive G i /G o proteins (1). Cellular signaling pathways regulated by ␣ 2A -AR in native cells include inhibition of adenylyl cyclase, activation of receptor-operated K ϩ channels, inhibition of voltage-gated Ca 2ϩ channels, and activation of the mitogen-activated protein kinase cascade (1-3). Many cells that express ␣ 2 -ARs are polarized, including renal and intestinal epithelia, where the ␣ 2 -AR serves to regulate sodium and water resorption (4, 5), as well as neurons, where these receptors act to suppress neurotransmitter release (6). The physiological functions mediated by ␣ 2 -ARs in polarized cells are dependent upon precise localization of the receptor at the basolateral surface to gain access to neurally delivered and blood-delivered catecholamines.The ␣ 2 -AR subtypes demonstrate unique targeting and retention profiles in polarized renal epithelial Madin-Darby canine kidney (MDCKII) cells in culture (7). Previous work in our laboratory has shown that the ␣ 2A -AR subtype is directly targeted to the basolateral surface, where it exhibits a half-life of 10 -12 h (8). Direct and exclusive basolateral targeting of ␣ 2A -AR was found to be dependent upon several noncontiguous regions within or near the bilayer, whereas retention of the receptor at the basolateral surface appears dependent upon the third intracellular (3i) loop (8). Deletion of the 3i loop results in accelerated surface turnover (t1 ⁄2 ϭ ϳ4.5 h) of the ␣ 2A -AR at the basolateral surface (9). Unlike the ␣ 2A -AR, the ␣ 2B -AR subtype is randomly targeted to both the apical and basolateral subdomains and then selectively retained at the basolateral surface of polarized MDCKII cells, where the receptor has a half-life comparable with that of the ␣ 2A -AR subtype (t1 ⁄2 ϭ ϳ10 -12 h) (7). Like for the ␣ 2A -AR, the 3i loop of the ␣ 2B -AR also is critical for basolateral surface stabilization of this subtype (10). In contrast to stable retention of the ␣ 2B -AR on the basolateral surface, the half-life on the apical surface is estimated to be

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“…Studies have confi rmed that α 1 -ARs are closely related to various diseases, such as hypertension, benign prostatic hyperplasia, prostate cancer, and so on (4)(5)(6). Therefore, it is extremely useful to develop drugs for diseases' examination and clinical diagnosis.…”

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confidence: 99%