Maladies dues aux prions

Maladies dues aux prion

Receptor regulation in neuronal cells

Desensitization is a property of almost all neurotransmitter and peptide receptors, which is always induced by the corresponding agonist. Desensitization plays an important role in the regulation of synaptic transmission, in limiting the duration of the post-synaptic response and in protecting the target neurons from excessive stimulation. There are several desensitization mechanisms which may be classified as “molecular” or “cellular”. Molecular desensitization may occur by changes in the receptor conformation, uncoupling of the receptor. Cellular desensitization, some aspects of which being not clearly distinct from the previous one, includes receptor internalization (also called receptor sequestration) and receptor down-regulation. In our laboratory, we have studied some aspects of the cellular regulation mechanisms of receptors, mainly internalization of muscarinic cholinergic and neurostensin receptors and the down-regulation of muscarinic, GABA-benzodiazepine, opiate (μ- and δ- subtypes), and neurotensin receptors. Molecular mechanisms of regulation are being more and more investigated at the genetic level and we will use these techniques to continue the study of neuroreceptor and peptide receptor regulation. Receptor internalization implies their activation by agonists, their clustering in coated pits and the formation of endocytic vesicles containing the receptors. Receptor down-regulation has been thought for a long time to result mainly from receptor degradation but more recently, a down-regulation of receptor mRNA was described after prolonged incubation in the presence of the agonist. The internalization of receptors may be followed either by their recycling or by their degradation but internalized receptors (or internalized ligand-receptor complexes) might also behave as “intracellular messengers” and might be involved in some delayed intracellular effects. This is what has been called recently “the third messenger system” where protein phosphorylation plays a key role (Bohmann, 1990; Huganir and Greengard, 1990; Whiting et al., 1990; Magnogi et al., 1991). Presently, very little is known concerning the signals that decide the intracellular desensitization, other consequences of receptor internalization in cellular physiology and in the control of cellular homeostasis are not clearly demonstrated. Internalized receptors may move by retrograde axonal transport towards the cell body and perhaps the nucleus membrane and it is tempting to imagine that these receptors might not only be destroyed at the end of this way but that they might bring some information useful for trophicity or plasticity of nerve cells. Agonist-induced regulation is a common property of different receptors for peptides, transmitters or drugs. It results in adaptation of the physiological or pharmacological responses and might be referred to as an additional criteria that has to be fulfilled for the definition of a functional receptor. In this work, we have integrated our results with the recent data from the literature and we discuss the interactions between different regulation mechanisms of the receptors. Drugs could influence receptor formation at the transcriptional (mRNA formation from DNA-, translational (protein synthesis from mRNA) or post-translational (protein phosphorylation, glycolysation …) stages and this could participate in both their long-term pharmacological and toxical effects. This is what might be called the “genomic pharmacology” which will become more and more important in the near futureThèse d'agrégation de l'enseignement supérieur (faculté de médecine) -- UCL, 199

La Commission d'Ethique Biomédicale Hospitalo-Facultaire de l' U.C.L.: Rôles et fonctionnement

La Commission d'Ethique Biomédicale Hospitalo-Facultaire de l' U.C.L.: Rôles et fonctionnemen

Agonist-induced muscarinic cholinergic receptor internalization, recycling and degradation in cultured neuronal cells : Cellular mechanisms and role in desensitization

Short-term incubation of intact neuronal cells with muscarinic cholinergic agonists resulted in a rapid decrease of the specific binding of [3H]methylscopolamine to cell surface receptors indicative of receptor internalization. The agonists induced the internalization of both the muscarinic receptor subtypes coupled to adenylyl cyclase and those coupled to phosphoinositide turnover. Receptor internalization, which was inhibited at 0-4 degrees and by depletion of intracellular K+, is thought to occur through coated pits formation and was rapidly reversible. Receptor recycling did not imply protein synthesis. Down-regulation of muscarinic receptors occurred slowly in the presence of agonists, needed intact cytoskeleton (demonstrated by the inhibitory effect of colchicine) and involved lysosomal activity. Both receptor internalization and down-regulation were prevented by muscarinic receptor antagonists. Receptor internalization and down-regulation are agonist-induced cellular mechanisms that with receptor phosphorylation and uncoupling, may induce desensitization. These processes may contribute to complex intracellular regulatory processes and may be involved in some of the long-term effects of neurotransmitters (mainly neuropeptides and growth hormones) or drugs

Mechanisms of regulation of neurotensin receptors.

Since its discovery in 1973, the neuropeptide neurotensin has been demonstrated to be involved in the control of a broad variety of physiological activities in both the central nervous system and in the periphery. Pharmacological studies have shown that the biological effects elicited by neurotensin result from its specific binding to cell membrane neurotensin receptors that have been characterized in various tissue and in cell preparations. In addition, it is now well documented that most of these responses are subject to rapid desensitization. Such desensitization results in transient responses to sustained peptide applications, or to tachyphylaxis during successive stimulations in the same conditions. More recently, desensitization of neurotensin signalling was investigated at the cellular and molecular levels. In cultured cells, regulation at the second messenger level, receptor internalization, and receptor down-regulation processes have been reported. These are proposed to play a critical role in the control of cell responsiveness to neurotensin. This review aims to compile recent data on the different biochemical processes involved in the regulation of the neurotensin receptor and to discuss the physiological consequences of this regulation in vivo

Lithium neurotoxicity at low therapeutic doses Hypotheses for causes and mechanism of action following a retrospective analysis of published case reports.

Lithium has been the pharmacologic treatment for the management of manic-depressive illness for many years. While the therapeutic efficacy of lithium is invaluable, it can cause a variety of neurotoxicities at normal therapeutic doses or concentrations. A systematic search through the Medline database was performed. 41 Cases of neurotoxic adverse effects of lithium at low therapeutic concentrations were observed ( 65 years, 6 females). Although a higher percentage of female subjects experienced lithium neurotoxicity, no statistically significant difference between the two groups was noted (Fisher's exact test, P = 0.07). The analysis of the data shows that among case reports of lithium neurotoxicity, drug interaction effect is an important factor. More than 50% (51.2%) of the patients received at least one neuroleptic medication with their lithium treatment, 22% received concomitantly an antidepressant, 22% an antiepileptic (carbamazepine) and 17% an anxiolytic. It is our hypothesis that these drug associations are an important contributing factor to lithium neurotoxicity. The high percentage of neurotoxicity which is associated with neuroleptics warrant caution in the daily clinical practice when these two classes of medications are combined. It is hypothesised that neuroleptics, in particular the phenothiazines, might increase lithium influx in red blood cells and that the enhanced levels of lithium in the tissue may possibly be responsible for the neurotoxic effects. Concomitant administration of medications such as neuroleptics with lithium require caution with regular clinical observations and drug plasma concentration monitoring