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Recio-Pinto E.,NYU Langone Medical Center | Castillo C.,Institute Estudios Avanzados IDEA
Techniques in Regional Anesthesia and Pain Management | Year: 2010

The role of N-methyl-D-aspartate receptors (NMDArs) in pain sensation was initially uncovered in 1987 when the hyperexcitability of spinal cord dorsal horn nociceptive neurons evoked by C-fiber stimulation was found to be blocked by spinal delivery of NMDAr antagonist. Since then, many studies have focused on the role of central NMDArs in pain sensation. It is now apparent that peripheral NMDArs also play a role not only in the initiation but also in the maintenance of chronic pain states, particularly those following peripheral nerve injuries. Peripheral NMDArs are an attractive target for treating chronic pain, because under normal (nonpainful) stimulation NMDArs in dorsal root ganglia (DRG) neurons do not activate; in addition, some of the NMDArs isoforms are predominantly expressed in DRG neurons, and NMDArs have various regulatory sites that are isoform-dependent. This article concentrates on reviewing the possible role of peripheral NMDArs in initiating and maintaining chronic pain states. Of particular interest is the role of NMDArs not only on peripheral DRG neurons but also on their surrounding glia, since neuronal-glial interactions have been shown to contribute to injury-evoked neuronal hyperexcitability. Drugs that would target selectively peripheral NMDArs would improve treatment of chronic pain states. This review is divided into 5 sections: NMDAr structure and function; the role of peripheral NMDArs in pain perception; modulation of NMDArs during pain states; modulation of NMDAr activity by Substance P; and role of glia in DRG neuronal hyperexcitability. © 2010.

Benaim G.,Institute Estudios Avanzados IDEA | Benaim G.,Central University of Venezuela | Paniz Mondolfi A.E.,Institute Biomedicina SAIB | Paniz Mondolfi A.E.,St Lukes Roosevelt Hospital Center
Nature Reviews Cardiology | Year: 2012

Chagas disease has emerged as an important health problem in the Americas and, with globalization, in other parts of the world. Drug therapy for this parasitic infection has remained largely ineffective, especially in chronic stages of the disease. However, developments in experimental therapy might signal an important advance for the management of patients with Chagas disease. Herein, we review studies on the potential use of the benzofuran derivatives amiodarone and dronedarone in patients with Chagas disease. These agents have a dual role, not only as primary antiarrhythmic drugs, but also as antiparasitic agents. We believe that this 'kill two birds with one stone' approach represents a new tactic for the treatment of Chagas disease using currently approved drugs. © 2012 Macmillan Publishers Limited. All rights reserved.

Rojas H.,Venezuelan Institute for Scientific Research | Colina C.,Venezuelan Institute for Scientific Research | Ramos M.,Venezuelan Institute for Scientific Research | Benaim G.,Institute Estudios Avanzados IDEA | And 3 more authors.
Advances in Experimental Medicine and Biology | Year: 2013

We have previously demonstrated that rat type-1 cerebellar astrocytes express a very active Na+/Ca2+ exchanger which accounts for most of the total plasma membrane Ca2+ fluxes and for the clearance of Ca i 2+ induced by physiological agonist. In this chapter, we have explored the mechanism by which the reverse Na +/Ca2+ exchange is involved in agonist-induced Ca 2+ signalling in rat cerebellar astrocytes. Laser-scanning confocal microscopy experiments using immunofluorescence labelling of Na +/Ca2+ exchanger and RyRs demonstrated that they are highly co-localized. The most important finding presented in this chapter is that L-glutamate activates the reverse mode of the Na+/Ca 2+ exchange by inducing a Na+ entry through the electrogenic Na+-glutamate co-transporter and not through the ionophoric L-glutamate receptors as confirmed by pharmacological experiments with specific blockers of ionophoric L-glutamate receptors, electrogenic glutamate transporters and the Na/Ca exchange. © Springer Science+Business Media New York 2013.

Stateva S.R.,Autonomous University of Madrid | Salas V.,Autonomous University of Madrid | Salas V.,Central University of Venezuela | Benaim G.,Central University of Venezuela | And 4 more authors.
PLoS ONE | Year: 2015

Calmodulin (CaM) phosphorylated at different serine/threonine and tyrosine residues is known to exert differential regulatory effects on a variety of CaM-binding enzymes as compared to non-phosphorylated CaM. In this report we describe the preparation and characterization of a series of phospho-(Y)-mimetic CaM mutants in which either one or the two tyrosine residues present in CaM (Y99 and Y138) were substituted to aspartic acid or glutamic acid. It was expected that the negative charge of the respective carboxyl group of these amino acids mimics the negative charge of phosphate and reproduce the effects that distinct phospho-(Y)-CaM species may have on target proteins. We describe some physicochemical properties of these CaM mutants as compared to wild type CaM, after their expression in Escherichia coli and purification to homogeneity, including: i) changes in their electrophoretic mobility in the absence and presence of Ca2+; ii) ultraviolet (UV) light absorption spectra, far- and near-UV circular dichroism data; iii) thermal stability in the absence and presence of Ca2+; and iv) Tb3+-emitted fluorescence upon tyrosine excitation. We also describe some biochemical properties of these CaM mutants, such as their differential phosphorylation by the tyrosine kinase c-Src, and their action as compared to wild type CaM, on the activity of two CaM-dependent enzymes: cyclic nucleotide phosphodiesterase 1 (PDE1) and endothelial nitric oxide synthase (eNOS) assayed in vitro. © 2015 Stateva et al.

Moller C.,Florida Atlantic University | Melaun C.,Biodiversity and Climate Research Center | Castillo C.,Institute Estudios Avanzados IDEA | Diaz M.E.,Queens Medical Research Institute | And 5 more authors.
Journal of Biological Chemistry | Year: 2010

Crustacean cardioactive peptide (CCAP) and related peptides are multifunctional regulatory neurohormones found in invertebrates. We isolated a CCAP-related peptide (conoCAP-a, for cone snail CardioActive Peptide) and cloned the cDNA of its precursor from venom of Conus villepinii. The precursor of conoCAP-a encodes for two additional CCAP-like peptides: conoCAP-b and conoCAP-c. This multi-peptide precursor organization is analogous to recently predicted molluscan CCAP-like preprohormones, and suggests a mechanism for the generation of biological diversification without gene amplification. While arthropod CCAP is a cardio-accelerator, we found that conoCAP-a decreases the heart frequency in Drosophila larvae, demonstrating that conoCAP-a and CCAP have opposite effects. Intravenous injection of conoCAP-a in rats caused decreased heart frequency and blood pressure in contrast to the injection of CCAP, which did not elicit any cardiac effect. Perfusion of rat ventricular cardiac myocytes with conoCAP-a decreased systolic calcium, indicating that conoCAP-a cardiac negative inotropic effects might be mediated via impairment of intracellular calcium trafficking. The contrasting cardiac effects of conoCAP-a and CCAP indicate that molluscan CCAP-like peptides have functions that differ from those of their arthropod counterparts. Molluscan CCAP-like peptides sequences, while homologous, differ between taxa and have unique sequences within a species. This relates to the functional hypervariability of these peptides as structure activity relationship studies demonstrate that single amino acids variations strongly affect cardiac activity. The discovery of conoCAPs in cone snail venom emphasizes the significance of their gene plasticity to have mutations as an adaptive evolution in terms of structure, cellular site of expression, and physiological functions. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

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