Human cloned alpha1A-adrenoceptor isoforms display alpha1L-adrenoceptor pharmacology in functional studies
| Autor: | David J. Chang, John D Lesnick, Jeffrey R. Jasper, David E. Clarke, Donald V. Daniels, George Stepan, Trena D. Meloy, Timothy J. Williams, Joel R Gever, Anthony P.D.W. Ford, M. Shannon Kava |
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| Rok vydání: | 1999 |
| Předmět: |
Cloning
Organism Inositol Phosphates Hamster CHO Cells Molecular cloning Pharmacology Biology In Vitro Techniques chemistry.chemical_compound Cricetinae Receptors Adrenergic alpha-1 Prazosin medicine Animals Humans Protein Isoforms Inositol Benzamide Inositol phosphate chemistry.chemical_classification Chinese hamster ovary cell In vitro Recombinant Proteins chemistry Biochemistry Adrenergic alpha-Agonists medicine.drug |
| Zdroj: | European journal of pharmacology. 370(3) |
| ISSN: | 0014-2999 |
| Popis: | The recombinant alpha1A-adrenoceptor displays a distinct pharmacological profile ('classical alpha1A-adrenoceptor') in homogenate binding assays, but displays the properties of the so-called alpha1L-adrenoceptor in functional studies in whole cells at 37 degrees C. As three splice variants of the human alpha1A-adrenoceptor have been described previously (alpha1A-1, alpha1A-2 and alpha1A-3), we have compared their functional pharmacological profiles, when expressed stably in Chinese hamster ovary (CHO-K1) cells (antagonist inhibition of noradrenaline-stimulated [3H]inositol phosphates accumulation). A fourth, novel isoform (alpha1A-4) has also been studied: alpha1A-4 mRNA predominates in several human tissues including prostate, liver, heart and bladder. In homogenate binding studies, all four isoforms displayed essentially identical affinity profiles, with prazosin (1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl)piperazine), tamsulosin (5-[2-[[2-(2-ethoxyphenoxy)ethyl]-amino]propyl]-2-methoxybenzen esulfonamide), RS-17053 (N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha,alphad imethyl-1H-indole-3-ethanamine hydrochloride), WB 4101 ((2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride) and 5-Me-urapidil (5-methyl-6[[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]amino]-1,3-d imethyuracil) all displaying subnanomolar affinities. In functional studies, noradrenaline accelerated [3H]inositol phosphates production with potencies (p[A]50) of between 5.8 and 6.6. The affinities of prazosin, RS-17053, WB 4101 and 5-Me-urapidil, at antagonizing responses to noradrenaline, were reduced by approximately 10-fold (cf. binding data), while those for tamsulosin and indoramin (N-[1-[2-(1H-indol-3-yl)ethyl]-4-piperidinyl]benzamide) remained constant or increased, consistent with the previously described alpha1L-adrenoceptor. Thus, all four human recombinant alpha1A-adrenoceptor isoforms display the pharmacology of the alpha1L-adrenoceptor when studied in functional assays, consistent with the hypothesis that the putative alpha1L-adrenoceptor represents a functional phenotype of the alpha1A-adrenoceptor. |
| Databáze: | OpenAIRE |
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