Xavier Guitart

Sigma receptors: biology and therapeutic potential

More than 20xa0years after the identification of the sigma receptors as a unique binding site in the brain and in the peripheral organs, several questions regarding this receptor are still open. Only one of the subtypes of the receptor has been cloned to date, but the endogenous ligand still remains unknown, and the possible association of the receptor with a conventional second messenger system is controversial. From the very beginning, the sigma receptors were associated with various central nervous system disorders such as schizophrenia or movement disorders. Today, after hundreds of papers dealing with the importance of sigma receptors in brain function, it is widely accepted that sigma receptors represent a new and different avenue in the possible pharmacological treatment of several brain-related disorders. In this review, what is known about the biology of the sigma receptor regarding its putative structure and its distribution in the central nervous system is summarized first. The role of sigma receptors regulating cellular functions and other neurotransmitter systems is also addressed, as well as a short overview of the possible endogenous ligands. Finally, although no specific sigma ligand has reached the market, different pharmacological approaches to the alleviation and treatment of several central nervous system disorders and deficits, including schizophrenia, pain, memory deficits, etc., are discussed, with an overview of different compounds and their potential therapeutic use.

Up-regulation of sigma1 receptor mRNA in rat brain by a putative atypical antipsychotic and sigma receptor ligand

Sigma(1) (sigma(1)) receptor mRNA expression was studied in the prefrontal cortex, striatum, hippocampus and cerebellum of rat brain by northern blot and in situ hybridization. The effects of a chronic treatment with antipsychotic drugs (haloperidol and clozapine), and with E-5842, a sigma(1) receptor ligand and putative atypical antipsychotic on sigma(1) receptor expression were examined. A significant increase in the levels of sigma(1) receptor mRNA in the prefrontal cortex and striatum after E-5842 administration was observed, while no apparent changes were seen with either haloperidol or clozapine. Our results suggest a long-term adaptation of the sigma(1) receptor at the level of mRNA expression in specific areas of the brain as a response to a sustained treatment with E-5842.

Regulation of Ionotropic Glutamate Receptor Subunits in Different Rat Brain Areas by a Preferential Sigma1 Receptor Ligand and Potential Atypical Antipsychotic

The effect of chronic administration of the putative atypical antipsychotic E-5842, a preferential sigma1 receptor ligand, on ionotropic glutamate receptor subunit levels of mRNA and protein, was studied. The repeated administration of E-5842 differentially regulated levels of the NMDA-2A and of GluR2 subunits in a regionally specific way. Levels of immunoreactivity for the NMDA-2A subunit were up-regulated in the medial prefrontal cortex, the frontoparietal cortex, the cingulate cortex, and in the dorsal striatum, while they were down-regulated in the nucleus accumbens. Levels of the GluR2 subunit of the AMPA receptor were up-regulated in the medial prefrontal cortex and the nucleus accumbens and down-regulation was observed in the dorso-lateral striatum. Regulation of the levels of mRNA for the different subunits was also observed in some cases. The results show that E-5842, through a mechanism still unknown, is able to modify levels of several glutamate receptor subunits and these changes could be related to its antipsychotic activity in pre-clinical tests.

Botulinum neurotoxin inhibits depolarization-stimulated protein phosphorylation in pure cholinergic synaptosomes

Botulinum neurotoxin, a strong blocker of acetylcholine release at peripheral cholinergic synapses, inhibits depolarization‐stimulated protein phosphorylation in pure cholinergic synaptosomes isolated from the electric organ of Torpedo marmorata. Moreover, tetrodotoxin has the same effect on protein phosphorylation when cholinergic synaptosomes are depolarized by veratridine. Correlation between presynaptic protein phosphorylation and acetylcholine release is suggested by the fact that botulinum neurotoxin blocks specifically neurotransmitter release without affecting membrane depolarization and calcium fluxes in our synaptosomal preparation.

Opiates depress ACh and ATP release from cholinergic synaptosomes by blocking calcium uptake.

We have studied the effects of opiates on ATP and acetylcholine (ACh) release from cholinergic nerve terminals isolated from the electric organ of Torpedo marmorata. The release of ATP was inhibited by morphine and this action was reversed by naloxone. Morphine, [D-Met2-Pro5]enkephalinamide and [D-Ala2-Leu5]enkephalin also inhibited acetylcholine release. Naloxone prevented these inhibitory effects. The action of enkephalin on ACh release was less effective than that of morphine. The calcium uptake by nerve terminals of Torpedo electric organ was also inhibited by morphine, either under resting or depolarizing conditions, and this effect was reversed by naloxone. Using the quick freeze-fracture method, the structural changes induced by morphine in the presynaptic membrane were also studied. Morphine prevents the rearrangement of intramembrane particles (IMPs) at both freeze-fractured faces of the synaptosomal presynaptic membrane after depolarization. It is concluded that opiates depress the ATP and the ACh releases from cholinergic synaptosomes by inhibiting the calcium uptake by the nerve terminals and the rearrangement of the IMPs after potassium-induced depolarization. Furthermore, ACh release, but not ATP release, seems to be related with the rearrangement of IMPs in the presynaptic membrane.

Changes in phosphoinositide signalling activity and levels of the alpha subunit of Gq/11 protein in rat brain induced by E-5842, a sigma1 receptor ligand and potential atypical antipsychotic

Changes in the phosphoinositide (PPI) signal transduction system induced by E-5842, a new sigma(1) (sigma(1)) receptor ligand and potential atypical antipsychotic, were studied in the rat frontal cortex, hippocampus and striatum. Acute treatment with E-5842 increased phospholipase C (PLC) activity in the striatum and the hippocampus. Chronic treatment with E-5842 induced an increase in the activity of PLC in the frontal cortex and the striatum. Similar up-regulation of the activity of the enzyme was also observed in rat frontal cortex membranes in presence of GTPgammaS. After chronic treatment with E-5842, it was also observed a significant increase of the immunoreactivity levels of G(q/11)alpha in the frontal cortex. Our results suggest that part of the antipsychotic effects of E-5842 could be related to the regulation of the PPI signal transduction pathway, especially after a prolonged treatment.

Depolarization-stimulated protein phosphorylation in pure cholinergic nerve endings

Cholinergic synaptosomes obtained from the electric organ of Torpedo marmorata have been used to study chemical stimulation-stimulated protein phosphorylation. Cholinergic synaptosomes were exposed to elevated K+0 concentrations or other chemical depolarizing agents such as gramicidin or secretagogues as the calcium ionophore A23187. During depolarization several synaptosomal proteins increase their state of phosphorylation. This phenomenon depends on the presence of Ca2+ in the external medium. These results suggest that stimulation of protein phosphorylation may be implicated in the acetylcholine release process and could represent a modulation mechanism in the neurotransmitter release machinery at this cholinergic synapse.

Periods of Modular GL2-type Abelian Varieties and p-adic Integration

ABSTRACT Let F be a number field and an integral ideal. Let f be a modular newform over F of level with rational Fourier coefficients. Under certain additional conditions, Guitart and colleagues [Guitart et al. 16] constructed a p-adic lattice which is conjectured to be the Tate lattice of an elliptic curve Ef whose L-function equals that of f. The aim of this note is to generalize this construction when the Hecke eigenvalues of f generate a number field of degree d ⩾ 1, in which case the geometric object associated with f is expected to be, in general, an abelian variety Af of dimension d. We also provide numerical evidence supporting the conjectural construction in the case of abelian surfaces.

The Effects of Botulinum Neurotoxin and Tetrodotoxin on Protein Phosphorylation in Pure Cholinergic Synaptosomes

Protein phosphorylation has been related to the molecular mechanisms of neurotransmitter release (1) and some phosphoproteins as Synapsin I are thought to be implicated in the exocytotic process (2). On the other hand, depolarization of isolated synaptic buttons (synaptosomes) results in the phosphorylation of specific proteins in rat brain synaptosomes (3) and in Torpedo electric organ synaptosomes (4). The electric organ of Torpedo is a useful model to study the acetylcholine release since it is innervated exclusively by cholinergic nerves (5), and presents an homologous structure with the neuromuscular junction. In contrast, in the electric organ of Torpedo the presynaptic nerve terminals represent as much as 2% to 3% of the total volume. A pure cholinergic synaptosomal fraction can be isolated from this organ (6). In these cholinergic synaptosomes the induced release of acetylcholine (7) and ATP (8) and the calcium fluxes (9) have been characterized. Acetylcholine release can be induced by several chemical depolarising agents as high external potassium concentration, or veratridine or the calcium ionophore A 23187. Botulinum toxin (BoNTx) blocks the acetylcholine release (see 10 and 11 for reviews) in several preparations. In cholinergic synaptosomes from the electric organ of Torpedo marmorata BoNTx inhibits the induced acetylcholine release whereas ATP release, calcium uptake and membrane potential are not affected by the toxin (12). We have used this pure cholinergic preparation to study the effect of botulinum neurotoxin type A under depolarising conditions on the rate of phosphorylation of synaptosomal proteins.