Irreversible inactivation of beta-adrenergic receptors of C6 glioma cells. Synthesis and study of a thiol derivative of propranolol |
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Authors: | H Gozlan V Homburger M Lucas J Bockaert R Michelot |
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Institution: | 1. Institute de Chimie des Substances Naturelles, C.N.R.S., 91190 Gif-sur-Yvette, France;2. Laboratoire de Physiologie Cellulaire, Collège de France, 75231 Paris Cedex 05, France |
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Abstract: | The beta-adrenergic receptor of C6 glioma cells contains a disulfide bridge which can be reduced by dithiothreitol (DTT). On intact cells, N-ethylmaleimide (NEM) (5 mM) does not change the affinity of 3H] H2-alprenolol (3H] DHA) but reduces the total number of beta-adrenergic cell receptors by 21 +/- 3 per cent ; (N = 3). After receptor reduction by DTT, NEM irreversibly blocks the accessibility of the beta-adrenergic receptors to 3H]DHA. On isolated membranes, incubation in the presence of either NEM (5 mM) or isoproterenol (5.10(-7) M) does not significantly modify the total number of beta-adrenergic receptors accessible to 3H]DHA. Incubation of membranes with both NEM and isoproterenol reduces the number of binding sites by 33 +/- 2 per cent ; (N = 3). A thiol derivative of propranolol was synthetized. Its affinity is 10 times lower than that of propranolol. This sulfur derivative reduces the total number of beta-adrenergic receptors by 22 +/- 3 per cent (N = 3) when incubated with the native receptor and by 55 +/- 4 per cent (N = 4) when incubated with the reduced receptor. DTT does not significantly reverse the blockade induced by propranolol-SH. A model is proposed for explaining these results. |
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Keywords: | Récepteurs β-adrénergiques DTT NEM Isoprotérénol antagoniste irréversible propranolol-SH β-adrenergic receptors DTT NEM isoproterenol irreversible-thiol antagonist (DTT) dithiothreitol DHA (NEM) N-ethyl maleimide |
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