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Hepatocyte homologous beta 2-adrenergic desensitization is associated with a decrease in number of plasma membrane
O Medina-Martínez1, J A García-Sáinz
1Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México D.F.
European Journal of Pharmacology
|January 15, 1993
Summary
Isoproterenol causes homologous beta-adrenergic desensitization in rat hepatocytes. This desensitization correlates with a loss of beta 2-adrenoceptors from the cell membrane, while remaining receptors stay functional.
Area of Science:
- Pharmacology
- Cell Biology
- Biochemistry
Background:
- Beta-adrenergic receptors mediate cellular responses to catecholamines.
- Homologous desensitization involves a loss of receptor function or number following prolonged agonist exposure.
- Hepatocytes are key cells in metabolic regulation and respond to adrenergic stimuli.
Purpose of the Study:
- To investigate the mechanism of homologous beta-adrenergic desensitization in rat hepatocytes.
- To determine the role of beta 2-adrenoceptor loss in this desensitization process.
- To assess the functional integrity of remaining receptors after desensitization.
Main Methods:
- Rat hepatocytes were preincubated with isoproterenol to induce desensitization.
- Cyclic AMP accumulation in whole cells and adenylyl cyclase activity in membranes were measured.
- Beta-adrenergic receptor density was assessed using [125I]iodocyanopindolol binding.
- Functional integrity was tested by guanine nucleotide modulation and alkaline phosphatase treatment.
- Cholera toxin-catalyzed ADP-ribosylation was used to assess G protein activity.
Main Results:
- Isoproterenol induced homologous desensitization, reducing cyclic AMP accumulation and adenylyl cyclase activity.
- Desensitization was quantitatively linked to a loss of beta 2-adrenoceptors from the plasma membrane.
- Remaining receptors maintained normal agonist affinity and guanine nucleotide modulation.
- Alkaline phosphatase treatment did not reverse desensitization, and ADP-ribosylation was not decreased.
- A slight increase in ADP-ribosylation was observed in desensitized cell membranes.
Conclusions:
- Homologous beta-adrenergic desensitization in hepatocytes is primarily mediated by a reduction in plasma membrane beta 2-adrenoceptor number.
- The remaining beta 2-adrenoceptors retain their functional capacity.
- Receptor loss, rather than post-receptor modifications like dephosphorylation or altered G protein activity, is the key event in this desensitization model.