Homologous β-adrenergic desensitization in isolated rat hepatocytes
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Abstract:
Hepatocytes from hypothyroid rats have a marked beta-adrenergic responsiveness. Preincubation of these hepatocytes with isoprenaline induced a time-dependent and concentration-dependent desensitization of the beta-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 beta-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 beta-adrenergic desensitization induced by isoprenaline.Keywords:
Homologous desensitization
Isoprenaline
Pindolol
This study characterized the rapid desensitization induced by arginine vasopressin (AVP) in vascular smooth muscle cells (VSMC) in culture. The Ca2+ mobilization response and, in some experiments, the intracellular pH changes were used as a probe for the desensitization phenomenon. In VSMC, AVP desensitization was homologous, concentration dependent, and occurred in less than 30 s. The desensitization was complete with 10(-7) M AVP. Receptor occupancy was a critical factor in the maintenance of desensitization, since complete hormone washing by acid glycine buffer produced an earlier (less than 5 min) recovery of the cell response, whereas partial hormone washing with saline (pH 7.4) required 15 min to produce any significant recovery. Protein kinase C activation was a significant mechanism in AVP desensitization, because protein kinase C downregulation inhibited the desensitization phenomenon. Receptor internalization was, however, not important for the desensitization phenomenon, since it still occurred at 4 degrees C. Treatment with pertussis toxin did not affect the Ca2+ mobilization response but decreased the AVP-mediated intracellular alkalinization, therefore suggesting that a Gi or Go protein may be involved in some but not all the aspects of the AVP signal transduction and the desensitization phenomena.
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Abstract G-protein-coupled chemoattractant receptors signal transiently upon ligand binding to effect cell orientation and motility but then are rapidly desensitized. The importance of desensitization has been unclear, because mutated nondesensitizable receptors mediate efficient chemotaxis. We hypothesized that homologous receptor desensitization is required for cellular navigation in fields of competing attractants. Modeling of receptor-mediated orientation shows that desensitization allows integration of attractant signals. Cells expressing normal receptors are predicted to 1) orient preferentially to distant gradients; 2) seek an intermediate position between balanced agonist sources; 3) and can be repositioned between chemoattractant-defined microenvironmental domains by modest changes in receptor number. In contrast, in the absence of desensitization, orientation is dominated by local agonist sources, precluding continued navigation. Furthermore, cell orientation in competing ligand gradients depends on the relative kinetic rates of receptor desensitization and recycling. We propose that homologous receptor desensitization is critical for cellular navigation in complex chemoattractant fields.
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Hepatocytes from hypothyroid rats have a marked beta-adrenergic responsiveness. Preincubation of these hepatocytes with isoprenaline induced a time-dependent and concentration-dependent desensitization of the beta-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 beta-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 beta-adrenergic desensitization induced by isoprenaline.
Homologous desensitization
Isoprenaline
Pindolol
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Homologous desensitization
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Three main pathways have been implicated in desensitization of receptors that stimulate adenylylcyclase (AC): cAMP-mediated phosphorylation; cAMP-independent phosphorylation, and receptor internalization. Cell lines derived from the murine Ltk- cell were found useful in exploring the contribution of cAMP-dependent phosphorylation in V2 vasopressin receptor desensitization. The HTB-2 cell expresses the human V2 vasopressin receptor, introduced by transfection of human genomic DNA, and the prostaglandin E1 (PGE1) receptor, endogenous to the Ltk- cell. The A7 cell expresses the hamster beta 2-adrenoceptor, which undergoes the above-mentioned desensitization processes. Treatment of HTB-2 cells with arginine-vasopressin (AVP) had no effect on AC responsiveness to PGE1, but promoted desensitization of the AVP response. This was seen as a 5-6-fold right shift in the dose-response curves for AVP action (cAMP accumulation in intact cells and AC stimulation in homogenates and isolated membranes) and in a decrease in the maximum effect of AVP on these parameters. AVP treatment caused a decrease in cell surface receptors to approximately 75% of control without changes in KD, as determined by Scatchard analysis. When cAMP was increased by treatment with 10 microM PGE1 and isobutylmethylxanthine, desensitization of the PGE1 receptor was observed but not of the AVP receptor. In A7 cells the same treatment caused, as expected, a 3-fold right shift in the dose-response curve for AC stimulation by isoproterenol, indicating that L cells can mediate heterologous desensitization. These data demonstrate that the V2 vasopressin and the PGE1 receptors undergo homologous desensitization in the absence of cAMP-mediated phosphorylation and that this component is not required for vasopressin receptor internalization.
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The patterns and mechanism of vascular desensitization to agonists were studied in isolated arteries of Wistar and SHR rats. The results showed that: (1) Arteries were much easier to desensitize peptidergic agonists (A II, AVP) than catecholaminer gic agonists (NE, PE); (2) the desensitization induced by peptidergic agonists and catecholaminer gic agonists were homologous within 30 minutes; (3) the endothelium-EDRF-cGMP pathway was not involved in agonist-induced desensitization; (4) inhibition of surface receptor internalization by phenylarsine oxide (PAO, 10(-5)mol/L) could transiently reverse the desensitization and the blocking of intracellular receptor re-insertion into the membrane by chloroauine (10(-5)mol/L) could accelerate the desensitization in varying degrees with different arteries, which demonstrated the involvement of receptor cycling in homologous desensitization, but was not the unique mechanism; (5) there was no change in the function of voltage-dependent Ca2+ channel during homologous desensitization; (6) the concentration-contraction curve of GTP gamma S shifted down-ward during homologous desensitization, suggesting the functional change of G protein (s); (7) the desensitization to agonists didn't decrease in arteries of SHR compared with the arteries of Wistar rats.
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Pindolol
Isoprenaline
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Alpha-1A adrenergic receptor
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Leucocytes from allergic donors were preincubated with suboptimal concentrations of ragweed or anti-IgE and then challenged with increasing concentrations of the homologous or heterologous agonist. The initial incubation resulted in desensitization, as judged by a reduced reactivity relative to controls preincubated without agonist but challenged similarly. Both homologous and heterologous desensitization were observed and were dose dependent. Evidence was obtained for both a reversible and irreversible component of desensitization, which was also agonist-concentration related. Reversibility occurred to a similar degree either by incubation of suboptimally desensitized cells with optimal concentrations of agonist or by removal of IgE and resensitization. This could implicate IgE-agonist aggregation on the basophil surface as a mechanism of desensitization. Histamine release from desensitized cells was highly correlated with degranulation, suggesting that individual cells were desensitized in an all-or-none manner.
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Beta-adrenergic receptor (β-AR)-mediated vasorelaxation declines with age. In the vasculature, β2-AR undergoes protein kinase A-mediated desensitization that causes a switch in the G protein coupled to β2-AR; Gαi links instead of Gαs. We exposed Fischer 344 rat aortae of increasing age to a desensitizing dose of isoproterenol, and determined its effect on β2-AR-mediated vasorelaxation. Desensitization decreased β2-AR-mediated vasorelaxation in young aortae only. Subsequently, we used pertussis toxin to block Gαi to determine whether changes in β2-AR/G protein coupling occurred. Gαi inhibition did not reverse desensitization or the age-related change, but there appears to be a population of β2-AR linked to Gαi, as pertussis toxin treatment improved β2-AR-mediated vasorelaxation in aortae from animals of all ages. These findings suggest aortic β2-AR in older animals may be maximally desensitized, which would explain impaired vasorelaxation. Our results also imply that protein kinase A-mediated β2-AR desensitization may not be responsible for the age-related decline.
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