Papers by Armando Alberola
por ligando (LGICs). Las disfunciones del nAChR se han relacionado con graves alteraciones fisiop... more por ligando (LGICs). Las disfunciones del nAChR se han relacionado con graves alteraciones fisiopatologicas del sistema nervioso, asi como con alteraciones inflamatorias e inmunologicas y con el desarrollo de ciertos tipos de cancer. Por ello, el conocimiento de las moleculas que modulan la funcion de este receptor, el estudio de sus mecanismos de accion y la dilucidacion de sus lugares de union son de gran interes cientifico, ya que son pasos fundamentales para avanzar en el desarrollo de nuevas moleculas de aplicacion terapeutica, dirigidas al tratamiento de las patologias mencionadas. Esta revision pretende describir los principales mecanismos de modulacion del nAChR y exponer los efectos que diversas moleculas de interes clinico ejercen sobre el nAChR, algunas inhibiendo su actividad y otras potenciandola. Armando Alberola-Die*, Sergi Soriano, Isabel Ivorra y Andres Morales
Un equipo multidisciplinar de profesores y profesoras que componen la Red Docente INVES e imparte... more Un equipo multidisciplinar de profesores y profesoras que componen la Red Docente INVES e imparten docencia en la asignatura Iniciacion a la Investigacion en Biologia, ha desarrollado una metodologia propia de trabajo en equipo, en coordinacion con el profesorado de la asignatura Estadistica, con la que se comparten objetivos de aprendizaje comunes. El sistema de evaluacion del trabajo colaborativo del alumnado se ha optimizado mediante el uso de rubricas y auto-evaluacion. Se ha propiciado la adquisicion de competencias transversales mediante una dinamica de trabajo en grupo. El diseno y desarrollo de un proyecto de investigacion bibliometrico, de tematica biologica, es realizado por los y las estudiantes, y culmina con la edicion de unas Jornadas Cientificas. Con el fin de mejorar la eficiencia de la evaluacion, se han consensuado criterios comunes de evaluacion continua entre el profesorado. Ello ha determinado un incremento de la capacidad de aprendizaje del alumnado a lo largo ...
Neuroscience of Nicotine, 2019
Muscle-type nicotinic acetylcholine receptors (nAChRms) belong to the Cys-loop subfamily of recep... more Muscle-type nicotinic acetylcholine receptors (nAChRms) belong to the Cys-loop subfamily of receptors and are key elements for synaptic transmission at the neuromuscular junction. There are two subtypes of nAChRms, differentially expressed during the lifetime, with their own structural, functional, and pharmacological characteristics. A broad number of structurally heterogeneous molecules, including endogenous molecules and compounds of therapeutic relevance, interact with the nAChRm and modulate its activity. These compounds act by different, not mutually exclusive, mechanisms: (i) competitive, interfering the binding of agonist to the orthosteric site; (ii) steric blockade, acting either into the channel pore or close to the orthosteric binding pocket; and (iii) allosteric, binding outside the orthosteric site and leading to decrease or enhance nAChRm function and so behaving as negative or positive allosteric modulators, respectively. Allosteric modulators might bind to different...
La elaboracion de materiales interactivos, a partir de preparaciones fisiologicas de las practica... more La elaboracion de materiales interactivos, a partir de preparaciones fisiologicas de las practicas de laboratorio de Fisiologia Animal-1, permitira a los alumnos alcanzar, de forma no presencial, competencias de especial complejidad, conceptual o metodologica, abordadas en las practicas experimentales. La generacion de estos materiales, mediante el uso de TICs, pondra a disposicion de los alumnos, a traves del Campus Virtual, simulaciones con protocolos experimentales interactivos que incluyan registros de variables fisiologicas adquiridos durante el desarrollo de practicas de laboratorio reales. Estas simulaciones constituyen un material didactico de especial relevancia en asignaturas en las que el tamano de los grupos de docencia practica es grande, como en Fisiologia Animal-1, lo que limita la participacion del alumno. El objetivo final es que estos materiales contribuyan a facilitar el aprendizaje no-presencial de los conceptos mas complejos y de determinadas habilidades, como l...
La modulacion de los canales activados por ligando (LGIC) por efectores alostericos es poco conoc... more La modulacion de los canales activados por ligando (LGIC) por efectores alostericos es poco conocida pero de gran interes, debido a la relacion existente entre la alteracion funcional de dichos canales y su implicacion en enfermedades neurodegenerativas como la enfermedad de Alzheimer. Este tipo de modulacion, mediada por un amplio espectro de moleculas endogenas y exogenas, anade una enorme complejidad a los mecanismos de senalizacion en los que intervienen dichas proteinas. Ademas, la multiplicidad de efectos sobre una misma molecula indica que hay diferentes lugares de union y mecanismos modulatorios alostericos. La hipotesis es que los anestesicos locales con grupos amino o amonio en su estructura molecular pueden mostrar una amplia variedad de efectos modulatorios sobre el receptor nicotinico de acetilcolina (nAChR). La lidocaina es un anestesico local cuya estructura molecular presenta un grupo amino terciario, susceptible de adquirir carga a pH fisiologico. El objetivo es est...
Internet pone a la disposicion del alumnado materiales educativos de calidad, pero el exceso de i... more Internet pone a la disposicion del alumnado materiales educativos de calidad, pero el exceso de informacion hace que buscarlos suponga una enorme inversion de tiempo. Ademas, el alumnado a veces no dispone de un criterio formativo adecuado de seleccion. El 83% de los usuarios de internet entre 18 y 29 anos, edad universitaria, participa en algun tipo de red social, lo que genera un compromiso con la comunidad virtual. Las redes sociales de mayor crecimiento en los ultimos anos corresponden a los tableros de seleccion de contenidos. Con todos estos datos, parece interesante que los docentes utilicen las TICs para crear una red social de contenidos seleccionados por el profesorado, como estrategia docente para poner a disposicion del alumnado recursos de excelencia que faciliten su aprendizaje; Esto requiere una inversion de tiempo y dinero muy inferior a los necesarios para el desarrollo de materiales especificos equivalentes. La herramienta Scliped permite formar redes sociales cola...
Durante el curso 2013-2014 se implemento en la asignatura de Fisiologia Animal I, del Grado en Bi... more Durante el curso 2013-2014 se implemento en la asignatura de Fisiologia Animal I, del Grado en Biologia de la Universidad de Alicante, un entorno personal de aprendizaje (EPA), a partir de la herramienta Scliped. Esta herramienta permitio desarrollar una red social de contenidos seleccionados por el profesorado, como estrategia docente para poner a disposicion del alumnado recursos de excelencia que faciliten su aprendizaje. La inversion de tiempo y dinero requerida fue sensiblemente inferior a la necesaria para el desarrollo de materiales especificos equivalentes. El alumnado tuvo a su disposicion un tablero de 130 contenidos seleccionados, distribuidos en 34 colecciones. Al finalizar el curso escolar 2013-2014, el EPA habia recibido un total de 60.794 visitas. La evaluacion del uso y conformidad del alumnado con esta herramienta mostro que, si bien opinaban que su uso era innovador, no podria sustituir la labor del profesorado. El porcentaje de adhesion a la herramienta fue bajo, ...
eLife, 2021
The voltage-gated potassium channel Kv1.3 plays an apparent dual physiological role by participat... more The voltage-gated potassium channel Kv1.3 plays an apparent dual physiological role by participating in activation and proliferation of leukocytes as well as promoting apoptosis in several types of tumor cells. Therefore, Kv1.3 is considered a potential pharmacological target for immunodeficiency and cancer. Different cellular locations of Kv1.3, at the plasma membrane or the mitochondria, could be responsible for such duality. While plasma membrane Kv1.3 facilitates proliferation, the mitochondrial channel modulates apoptotic signaling. Several molecular determinants of Kv1.3 drive the channel to the cell surface, but no information is available about its mitochondrial targeting. Caveolins, which are able to modulate cell survival, participate in the plasma membrane targeting of Kv1.3. The channel, via a caveolin-binding domain (CBD), associates with caveolin 1 (Cav1), which localizes Kv1.3 to lipid raft membrane microdomains. The aim of our study was to understand the role of such...
International Journal of Molecular Sciences
Fritillaria bulbs are used in Traditional Chinese Medicine to treat several illnesses. Peimine (P... more Fritillaria bulbs are used in Traditional Chinese Medicine to treat several illnesses. Peimine (Pm), an anti-inflammatory compound from Fritillaria, is known to inhibit some voltage-dependent ion channels and muscarinic receptors, but its interaction with ligand-gated ion channels remains unexplored. We have studied if Pm affects nicotinic acetylcholine receptors (nAChRs), since they play broad functional roles, both in the nervous system and non-neuronal tissues. Muscle-type nAChRs were incorporated to Xenopus oocytes and the action of Pm on the membrane currents elicited by ACh (IAChs) was assessed. Functional studies were combined with virtual docking and molecular dynamics assays. Co-application of ACh and Pm reversibly blocked IACh, with an IC50 in the low micromolar range. Pm inhibited nAChR by: (i) open-channel blockade, evidenced by the voltage-dependent inhibition of IAch, (ii) enhancement of nAChR desensitization, revealed by both an accelerated IACh decay and a decelerate...
Neuroscience
Most local anesthetics (LAs) are amine compounds bearing one or several phenolic rings. Many of t... more Most local anesthetics (LAs) are amine compounds bearing one or several phenolic rings. Many of them are protonated at physiological pH, but benzocaine (Bzc) is permanently uncharged, which is relevant because the effects of LAs on nicotinic acetylcholine (ACh) receptors (nAChRs) depend on their presence as uncharged or protonated species. The aims of this study were to assess the effects of Bzc on nAChRs and to correlate them with its binding to putative interacting sites on this receptor. nAChRs from Torpedo electroplaques were microtransplanted to Xenopus oocytes and currents elicited by ACh (IAChs), either alone or together with Bzc, were recorded at different potentials. Co-application of ACh with increasing concentrations of Bzc showed that Bzc reversibly blocked nAChRs. IACh inhibition by Bzc was voltage-independent, but the IACh rebound elicited when rinsing Bzc suggests an open-channel blockade. Besides, ACh and Bzc co-application enhanced nAChR desensitization. When Bzc was just pre-applied it also inhibited IACh, by blocking closed (resting) nAChRs. This blockade slowed down the kinetics of both the IACh activation and the recovery from blockade. The electrophysiological results indicate that Bzc effects on nAChRs are similar to those of 2,6-dimethylaniline, an analogue of the hydrophobic moiety of lidocaine. Furthermore, docking assays on models of the nAChR revealed that Bzc and DMA binding sites on nAChRs overlap fairly well. These results demonstrate that Bzc inhibits nAChRs by multiple mechanisms and contribute to better understanding both the modulation of nAChRs and how LAs elicit some of their clinical side effects. This article is part of a Special Issue entitled: SI: Miledi's contributions. Item Group Code: IG005160.
Frontiers in molecular neuroscience, 2018
Nicotinic acetylcholine (ACh) receptors (nAChRs) are included among the targets of a variety of l... more Nicotinic acetylcholine (ACh) receptors (nAChRs) are included among the targets of a variety of local anesthetics, although the molecular mechanisms of blockade are still poorly understood. Some local anesthetics, such as lidocaine, act on nAChRs by different means through their ability to present as both charged and uncharged molecules. Thus, we explored the mechanisms of nAChR blockade by tetracaine, which at physiological pH is almost exclusively present as a positively charged local anesthetic. The nAChRs from electroplaques were transplanted to oocytes and the currents elicited by ACh ( s), either alone or co-applied with tetracaine, were recorded. Tetracaine reversibly blocked , with an (i.e., the concentration required to inhibit half the maximum ) in the submicromolar range. Notably, at very low concentrations (0.1 μM), tetracaine reduced in a voltage-dependent manner, the more negative potentials produced greater inhibition, indicating open-channel blockade. When the tetrac...
Frontiers in molecular neuroscience, 2016
To identify the molecular determinants responsible for lidocaine blockade of muscle-type nAChRs, ... more To identify the molecular determinants responsible for lidocaine blockade of muscle-type nAChRs, we have studied the effects on this receptor of 2,6-dimethylaniline (DMA), which resembles lidocaine's hydrophobic moiety. Torpedo marmorata nAChRs were microtransplanted to Xenopus oocytes and currents elicited by ACh (IACh), either alone or co-applied with DMA, were recorded. DMA reversibly blocked IACh and, similarly to lidocaine, exerted a closed-channel blockade, as evidenced by the enhancement of IACh blockade when DMA was pre-applied before its co-application with ACh, and hastened IACh decay. However, there were marked differences among its mechanisms of nAChR inhibition and those mediated by either the entire lidocaine molecule or diethylamine (DEA), a small amine resembling lidocaine's hydrophilic moiety. Thereby, the IC50 for DMA, estimated from the dose-inhibition curve, was in the millimolar range, which is one order of magnitude higher than that for either DEA or li...
Frontiers in Molecular Neuroscience, 2016
Neuroscience Research, 2013
Lidocaine is a commonly used local anaesthetic that, besides blocking voltage-dependent Na + chan... more Lidocaine is a commonly used local anaesthetic that, besides blocking voltage-dependent Na + channels, has multiple inhibitory effects on muscle-type nicotinic acetylcholine (ACh) receptors (nAChRs). In the present study, we have investigated the effects of lidocaine on ACh-elicited currents (I ACh s) from cultured mouse superior cervical ganglion (SCG) neurons, which mainly express heteromeric α3β4 nAChRs. Neurons were voltage-clamped by using the perforated-patch method and I ACh s were elicited by fast application of ACh (100-300 µM), either alone or in presence of lidocaine at different concentrations. I ACh s were reversibly blocked by lidocaine in a concentration-dependent way (IC 50 = 41 µM; n H close to 1) and the inhibition was, at least partially, voltage-dependent, indicating an open-channel blockade. Besides, lidocaine blocked resting (closed) nAChRs, as evidenced by the increased inhibition caused by a 12 s lidocaine application just before its co-application with the agonist, and also enhanced I ACh s desensitisation, at concentrations close to the IC 50. These results indicate that lidocaine has diverse inhibitory actions on neuronal heteromeric nAChRs resembling those previously reported for Torpedo (muscle-type) nAChRs (Alberola-Die et al., 2011). The similarity of lidocaine actions on different subtypes of heteromeric nAChRs differs with the specific effects of other compounds, restricted to particular subtypes of nAChRs.
Journal of Neurochemistry, 2011
Nicotinic acetylcholine (ACh) receptors (nAChRs) belong to the 'Cys-loop' superfamily of ligand-g... more Nicotinic acetylcholine (ACh) receptors (nAChRs) belong to the 'Cys-loop' superfamily of ligand-gated ion channels and are widely expressed in the central and peripheral nervous systems (Albuquerque et al. 2009; Taly et al. 2009). In humans, nAChR dysfunctions have been implicated in a variety of severe pathologies, including certain types of epilepsy, myasthenic syndromes, schizophrenia and Parkinson's and Alzheimer's diseases (Gotti and Clementi 2004; Sacco et al. 2004; Dani and Bertrand 2007; Steinlein and Bertrand 2010). Thus, the study of the mechanisms by which different drugs modulate nAChR function is of great interest not only for expanding our knowledge on the function of this receptor protein but also for developing new therapeutic molecules which might be useful for the treatment of nAChR-involved pathologies. A variety of compounds, including the quaternaryammonium cholinesterase inhibitors 1,5-bis(4-allyldimethylammoniumphenyl)pentan-3-one dibromide (BW284c51), decamethonium or edrophonium (Olivera-Bravo et al. 2005, 2007), and the local anaesthetics (LAs) 2-(triethylammonio)-N-(2,6-dimethylphenyl) acetamide bromide (QX-314), 2-(trimethylammonio)-N-(2,6-dimethylphenyl) acetamide chloride (QX-222), tetracaine, proadifen, lidocaine, adiphenine or procaine (
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Papers by Armando Alberola