Mechanisms for the emergence of catecholamine-sensitive adenylate cyclase and β-adrenergic receptors in cultured hepatocytes (original) (raw)
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European Journal of Pharmacology: Molecular Pharmacology, 1993
Long-term effects of cAMP on the surface expression of/3-adrenoceptors and adenylyl cyclase activity were investigated in primary cultures of rat hepatocytes. /3-Adrenoceptor density and catecholamine-responsive adenylyl cyclase activity increased during culturing in a biphasic manner, with a plateau of 10-20 h duration occurring approximately 10 h after plating. Treatment of hepatocyte cultures with 8-bromo-cAMP during the plateau period did not affect the density of/3-adrenoceptors. In contrast, addition of 8-bromo-cAMP, 8-chlorophenylthio-cAMP, forskolin or glucagon during a period of active recruitment of surface /3-adrenoceptors resulted in a suppression of the acquisition of fl-adrenoceptors. In both experimental situations there was a partial decrease in hormone-stimulated and basal adenylyl cyclase activity. The results suggest that cAMP exerts at least two types of long-term regulation of adenylyl cyclase in hepatocytes: a suppressive effect on fl-adrenoceptor acquisition, and a partial, nonselective decrease in adenylyl cyclase activity not involving /3-adrenoceptor down-regulation.
Homologous β-adrenergic desensitization in isolated rat hepatocytes
Biochemical Journal, 1987
Hepatocytes from hypothyroid rats have a marked fl-adrenergic responsiveness. Preincubation of these hepatocytes with isoprenaline induced a time-dependent and concentration-dependent desensitization of the ,3-adrenergic responsiveness without altering that to glucagon (homologous desensitization). The desensitization was evidenced both in the cyclic AMP accumulation and in the stimulation of ureagenesis induced by the /3-adrenergic agonists. Under the same conditions, preincubation with glucagon induced no desensitization. Propranolol was also unable to induce desensitization, but blocked that induced by isoprenaline. Pertussis-toxin treatment did not alter the homologous fl-adrenergic desensitization induced by isoprenaline. * To whom reprint requests should be addressed.
European Journal of Pharmacology: Molecular Pharmacology, 1993
Preincubation of rat hepatocytes with isoproterenol induces homologous /3-adrenergic desensitization evidenced both in whole ceils (cyclic AMP accumulation) and membranes (adenylyl cyclase activity). This desensitization is associated with and quantitatively similar to a loss of/32-adrenoceptors from the plasma membrane. Desensitization did not alter the affinities of isoproterenol for the [azsI]iodocyanopindolol binding sites nor reduce the ability of guanine nucleotides to modulate agonist affinity, i.e., the receptors that remain in the surface of plasma membrane after desensitization (= 50%) retain their functional integrity. When membranes from isoproterenol-desensitized hepatocytes were treated with alkaline phosphatase, no attenuation of the desensitization was observed. Cholera toxin-catalyzed ADP-ribosylation was not decreased but rather slightly increased in membranes from desensitized cells as compared to the controls. Our data indicate that in hepatocytes, a loss of/32-adrenoceptors from the plasma membrane is closely associated to the homologous desensitization induced by isoproterenol.
Elevated level of β-adrenergic receptors in hepatocytes from regenerating rat liver
Experimental Cell Research, 1986
Hepatocytes from regenerating rat liver show an enhanced epinephrine-sensitive adenylate cyclase activity and CAMP response, which may be involved in triggering of the cell proliferation. We have determined adrenergic receptors and adenylate cyclase activity in hepatocytes isolated at various time points after partial hepatectomy. The number of /?adrenergic receptors, measured by binding of ['251]iodocyanopindolol (['*'I]CYP) to a particulate fraction prepared from isolated hepatocytes, increased rapidly after partial hepatectomy as compared with sham-operated or untreated controls. The maximal increase, which was observed at 48 h, was between 5-and 6-fold (from -1800 to -10500 sites per cell). Thereafter, the number of j3-adrenergic receptors decreased gradually. Competition experiments indicated /12-type receptors. Parallelism was found between the change in the number of b2-adrenergic receptors and the isoproterenol-responsive adenylate cyclase activity. The number of a,-adrenergic receptors, determined by binding of [3H]prazosin, was transiently lowered by about 35 % at 18-24 h, with no significant change in Kd. Although the results of this study do not exclude the possibility of post-receptor events, they suggest that the increased number of P2-adrenergic receptors is a major factor responsible for the enhanced catecholamine-responsive adenylate cyclase activity in regenerating liver.
Adrenergic agonists induce heterologous sensitization of adenylate cyclase in NS20Y-D2L cells
FEBS Letters, 2001
Adenylate cyclase activity in NS20Y cells expressing D 2L dopamine receptors was examined following chronic treatment with norepinephrine and epinephrine. Initial acute experiments revealed that both norepinephrine and epinephrine inhibited forskolin-stimulated cyclic AMP accumulation via D 2 receptors. Furthermore, chronic (18 h) activation of D 2 dopamine receptors by norepinephrine or epinephrine induced a marked increase (s 10-fold) in subsequent forskolin-stimulated cyclic AMP accumulation. This heterologous sensitization of adenylate cyclase activity was blocked by D 2 dopamine receptor antagonists and by pertussis toxin pretreatment. In contrast, concurrent activation of GK K s or adenylate cyclase did not appear to alter noradrenergic agonist-induced sensitization. ß 2001 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.
British Journal of Pharmacology, 1977
I The /i-adrenoceptor agonist isoprenaline normally causes only a small and inconsistent increase in the membrane potential of cells in guinea-pig liver slices, in contrast to the large hyperpolarizations seen with a-agonists. However, after a selective a-adrenoceptor agonist has been applied, the response to isoprenaline becomes greatly enhanced. 2 Simultaneous application of small doses of an a-and a P-agonist produce hyperpolarizations larger than the sum of the responses to each agent alone. 3 These interactions occur with a range of sympathomimetic amines, including some which are not substrates for various processes for the uptake and inactivation of catecholamines. 4 Hyperpolarizations caused by externally applied cyclic adenosine-3',5'-monophosphate (cyclic AMP) also become larger after application of an a-agonist. 5 The adenine nucleotides adenosine 5'-diphosphate (ADP) and adenosine 5'-triphosphate (ATP) hyperpolarize guinea-pig liver cells in the dose range 0.1-1.0 mM. This response is not increased after an a-agonist. However, ADP and ATP are themselves able to enhance the response to f-agonists. 6 These interactions between a-agonists, P-agonists and adenine nucleotides seem to involve steps subsequent to receptor activation. Changes in the intracellular actions of cyclic AMP may be concerned.
Desensitization of β-adrenergic receptor-coupled adenylate cyclase activity
Biochemical Pharmacology, 1984
The effects on the Padrenergic receptors of intact L6 muscle cells of exposure to agonists were investigated. Treatment of cells with isoproterenol decreased GTP-, isoproterenol-, and zinterolstimulated adenylate cyclase activities, whereas exposure of cells to zinterol decreased only isoproterenol-