<p>The alpha-2 adrenergic receptor (α<sub>2</sub>-AR) subfamily includes three different subtypes, α<sub>2A</sub>-, α<sub>2B</sub>- and α<sub>2C</sub>-AR, all believed to exert their function through heterotrimeric G<sub>i/o</sub>-proteins. The present study was undertaken in order to investigate subtype differences in terms of cellular response and to explore other potential signalling pathways of α<sub>2</sub>-ARs.</p><p>Evidence is provided for a strong G<sub>s</sub>-protein coupling capability of the α<sub>2B</sub>-AR, leading to stimulation of adenylyl cyclase (AC). The difference between the α<sub>2A</sub>- and α<sub>2B</sub>-AR subtypes, in this respect, was shown to be due to differences in the second intracellular loops of the receptor proteins. Substitution of the second loop in α<sub>2A</sub>-AR with the corresponding domain of α<sub>2B</sub>-AR enrolled the chimeric α<sub>2A</sub>/α<sub>2B</sub> receptor with functional α<sub>2B</sub>-AR properties. Dual G<sub>i</sub> and G<sub>s</sub> coupling can have different consequences for AC output. Using coexpression of receptors and G-proteins, it was shown that the ultimate cellular response of α<sub>2B</sub>-AR activation is largely dependent on the ratio of G<sub>i</sub>- to G<sub>s</sub>-protein amounts in the cell. Also G<sub>i</sub>- and G<sub>o</sub>-proteins appear to have different regulatory influences on AC. Heterologous expression of AC2 together with G<sub>i</sub> or G<sub>o</sub> and the α<sub>2A</sub>-AR resulted in receptor-mediated inhibition of protein kinase C-stimulated AC2 activity through G<sub>o</sub>, whereas activation of G<sub>i</sub> potentiated the activity. </p><p>α<sub>2</sub>-ARs mobilize Ca<sup>2+</sup> in response to agonists in some cell types. This response was shown to depend on tonic purinergic receptor activity in transfected CHO cells. Elimination of the tonic receptor activity almost completely inhibited the Ca<sup>2+</sup> response of α<sub>2</sub>-ARs.</p><p>In conclusion, α<sub>2</sub>-ARs can couple to multiple G-proteins, including G<sub>i</sub>, G<sub>o</sub> and G<sub>s</sub>. The cellular response to α<sub>2</sub>-AR activation depends on which receptor subtype is expressed, which cellular signalling constituents are engaged (G-proteins and effectors), and the signalling status of the effectors (dormant or primed).</p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-1569 |
| Date | January 2001 |
| Creators | Näsman, Johnny |
| Publisher | Uppsala University, Department of Physiology, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, text |
| Relation | Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 0282-7476 ; 1105 |
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