Modulation of alpha2-adrenoceptor functions by heterotrimeric Galphai protein isoforms
| Autor: | Johanna Schneider, Julián Albarrán-Juárez, Bernd Nürnberg, Katja Pexa, Lutz Hein, Lutz Birnbaumer, Roland P. Piekorz, Nadine Beetz, Ralf Gilsbach |
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| Rok vydání: | 2009 |
| Předmět: |
Agonist
Gene isoform Male medicine.medical_specialty medicine.drug_class G protein Gi alpha subunit Stimulation Biology GTP-Binding Protein alpha Subunits Gi-Go Motor Activity Mice Norepinephrine Neuropharmacology Receptors Adrenergic alpha-2 Internal medicine Heterotrimeric G protein medicine Adrenergic alpha-2 Receptor Agonists Animals Protein Isoforms Receptor Pharmacology Mice Knockout Brain Medetomidine Heterotrimeric GTP-Binding Proteins Cell biology Mice Inbred C57BL Endocrinology Molecular Medicine Signal transduction |
| Zdroj: | Albarran-Juarez, J, Gilsbach, R, Piekorz, R P, Pexa, K, Beetz, N, Schneider, J, Nurnberg, B, Birnbaumer, L & Hein, L 2009, ' Modulation of 2-Adrenoceptor Functions by Heterotrimeric G i Protein Isoforms ', Journal of Pharmacology and Experimental Therapeutics . https://doi.org/10.1124/jpet.109.157230 |
| ISSN: | 1521-0103 |
| DOI: | 10.1124/jpet.109.157230 |
| Popis: | Subtype diversity of heterotrimeric G proteins and G protein-coupled receptors enables a wide spectrum of signal transduction. However, the significance of isoforms within receptor or G protein subfamilies has not been fully elucidated. In the present study, we have tested whether alpha(2)-adrenoceptors require specific Galpha isoforms for their function in vivo. In particular, we analyzed the role of the highly homologous Galpha(i) isoforms, Galpha(i1), Galpha(i2), and Galpha(i3), in typical alpha(2)-adrenoceptor-controlled functions. Mice with targeted deletions in the genes encoding Galpha(i1), Galpha(i2), or Galpha(i3) were used to test the effects of alpha(2)-adrenoceptor stimulation by the agonist medetomidine. The alpha(2)-adrenoceptor agonist medetomidine inhibited [(3)H]norepinephrine release from isolated prefrontal brain cortex or cardiac atria tissue specimens with similar potency and efficacy in tissues from wild-type or Galpha(i)-deficient mice. In vivo, bradycardia, hypotension, induction of sleep, antinociception, and hypothermia induced by alpha(2)-adrenoceptor activation did not differ between wild-type and Galpha(i)-knockout mice. However, the effects of the alpha(2)-agonists medetomidine or 5-bromo-6-(2-imidazolin-2-ylamino)quin-oxaline tartrate (UK14,304) on spontaneous locomotor activity or anesthetic sparing were reduced or absent, respectively, in mice lacking Galpha(i2). In microdissected locus coeruleus neurons or postganglionic sympathetic neurons from stellate ganglia, all three Galpha(i) subunits were expressed as determined by quantitative reverse transcription-polymerase chain reaction, with Galpha(i1) and Galpha(i2) dominating over Galpha(i3). Functional redundancy of the highly homologous Galpha(i) isoforms may predominate over specificity to regulate distinct intracellular pathways downstream of alpha(2)-adrenoceptors in vivo. In contrast, inhibition of locomotor activity and anesthetic sparing may be elicited by a specific coupling of alpha(2A)-adrenoceptors via the Galpha(i2) isoform to intracellular pathways. |
| Databáze: | OpenAIRE |
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