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3. 37P TreatMYPN: In vivo mouse characterization and in vitro 3D muscle studies followed by 15P AAV gene therapy for the ultrarare myopalladin-related congenital myopathy.

Author

Onnée, M., Taglietti, V., Gicquel, E., Bastu, S., Periou, B., Banos, G., Mignot, J., Bleuzen, A., Roudaut, C., Tiret, L., Didier, N., Richard, I., Relaix, F., and Malfatti, E.

Subjects
*MUSCLE weakness, *GENE therapy, *SATELLITE cells, *SKELETAL muscle, *GRIP strength, *NEMALINE myopathy
Abstract

Myopalladin-related congenital myopathy (MYPN-CM) is an ultrarare disorder characterized by skeletal muscle weakness, nemaline bodies and caps in muscle biopsies, linked to biallelic MYPN gene variants. Due to its rarity, MYPN-CM is not a target for drug development by pharmaceutic companies. Investigations using a Mypn knockout (MKO) mouse model have revealed that myopalladin is involved in maintaining sarcomere integrity and muscle functionality but its exact functions are unknown. We thus further explored MKO models to delineate disease mechanisms through detailed functional and transcriptomic analyses, and to pioneer an adeno-associated virus (AAV) gene therapy approach both in vitro and in vivo. Using muscle 3D organoids derived from mice satellite cells, we observed that MKO myofibers exhibited Z-lines disarray and α-actinin accumulation reminding of caps, and prominent nuclear centralizations not observed in wild-type myofibers. MKO functional analysis showed significant and unreported grip strength deficits mirroring patients' muscular weakness. To set up AAV gene therapy strategy we designed an AAV vector integrating the full-sized MYPN gene preceded by a skeletal muscle specific promoter. The goal is to introduce a functional MYPN gene directly into muscle cells, striving to rectify the abnormal muscle function and counteract the pathological features noted in MKO models, both in vitro and in vivo. This approach holds promise for accurately modeling ultra-rare diseases and potentially lead to a n-of-1 patient clinical trial that can be transitioned into clinical practice. [ABSTRACT FROM AUTHOR]

Published
2024
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5. DMD - BIOMARKERS

Author

Cardone, N., primary, Taglietti, V., additional, Kefi, K., additional, Periou, P., additional, Gitiaux, C., additional, Traverso, M., additional, Panicucci, C., additional, Baratto, S., additional, Authier, J., additional, Bruno, C., additional, Lafuste, P., additional, Fiorillo, C., additional, Relaix, F., additional, and Malfatti, E., additional

Published
2021
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8. Creating Coordination in the Cerebellum Catania, 2–4 October 2003

Author

Andjus, P. R., Zhu, L., Strata, P., Arata, A., Ito, M., Bearzatto, B., Servais, L., Baba-Aïssa, F., de Kerchove d’Exaerde, A., Schurmans, S., Cheron, G., Schiffmann, S. N., Bower, J. M., Devor, A., Burguière, E., Rutteman, M., De Zeeuw, C. I., Berthoz, A., Wiener, S., Rondi-Reig, L., Campana, A., Dusart, I., Wherlé, R., Weitzman, J., Yaniv, M., Sotelo, C., Mariani, J., Cavallari, P., Esposti, R., Cerri, G., Cerminara, N. L., Apps, R., Marple-Horvat, D. E., Wagstaff, J., Dan, B., Chorev, E., Manor, Y., Sohl, G., Willecke, K., Yarom, Y., Philipona, D., Dognin, E., Coenen, O. J., Sola, E., Prestori, F., Rossi, P., Taglietti, V., D’Angelo, E., De Filippi, G., Baldwinson, T., Sher, E., Ekerot, C., Jorntell, H., Fernández, G., Martínez, S., Gall, D., Roussel, C., Forti, L., Schiffmann, S., Gruol, D. L., Netzeband, J. G., Quina, L. A., Blakely Gonzalez, P. K., Hoebeek, F. E., Van Alphen, A. M., Schonewille, M., Frens, M. A., Goossens, H. H. L. M., Stahl, J., Ango, F., di Cristo, G., Hagashiyama, H., Bennett, V., Huang, Z. J., Jörntell, H., Ekerot, C.- F., Launey, T., Endo, S., Sakai, R., Harano, J., Lohof, A. M., Sherrard, R. M., Lu, H., Huang, C., Hartmann, M. J., Marshall, S. P., Lang, E. J., Michikawa, T., Mikoshiba, K., Nitschke, M. F., Erdmann, C., Melchert, U., Arp, T., Sprenger, A., Petersen, D., Kömpf, D., Binkofski, F., Heide, W., Pedroarena, C., Schwarz, C., Parsons, L. M., Schmahmann, J. D., Grill, S. E., Walker, M. S., Petacchi, A., Rokni, D., Saito, S., Kato, K., Sajdel-Sulkowska, E. M., Nguon, K., Selimi, F., Wang, Q., Cristea, I., Chait, B., Heintz, N., Serapide, M. F., Cicirata, F., De Saedeleer, C., Schwaller, B., Swinny, J. D., Ijkema-Paassen, J., Metzger, F., Kalicharan, D., Gramsbergen, A., van der Want, J. J. L., Slemmer, J. E., Weber, J. T., Winkelman, B. H. J., Chédotal, A., De Schutter, E., Maex, R., Koekkoek, S. K. E., Bouslama, L., Ghoumari, A., Ebner, T., Häusser, M., Hawkes, R., Herrup, K., Lisberger, S. G., Mugnaini, E., Nunzi, M. -G., Russo, M., Ptak, K., Orr, H. T., Zoghbi, H. Y., Rossi, F., Ruigrok, T. J. H., Sabel-Goedknegt, E., Simpson, J. I., Morando, L., Cesa, R., Dumoulin, A., Dieudonné, S., Dugué, G., Triller, A., Louvi, A., Alexandre, P., Wurst, W., and Wassef, M.

Published
2004
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11. Abstract

Author

Andries, L. J., Sys, S. U., Meulemans, A. L., Schuurkes, J. A. J., Vanheel, B., Van de Voorde, J., De Smet, P., Li, J., Van Driessche, W., Flamion, B., Foulon, S., Abramow, M., Calders, P., Eechaute, W., Lacroix, E., Weyne, I., Hoeben, D., Burvenich, C., Fransen, P., Andries, L. J., Van Bedaf, D., Demolder, M., Sys, S. U., Ouedraogo, R., Lebrun, P., Herchuelz, A., Antoine, M. -H., Vandenput, S., Votion, D., Anciaux, N., Duvivier, D. H., Art, T., Lekeux, P., Votion, D., Ghafir, Y., Vandenput, S., Art, T., Lekeux, P., Geurts, M., Hermans, E., Maloteaux, J. -M., Perrad, B., Noel, B., Lagache, F., Bister, J. L., Paquay, R., Bister, J. L., Derycke, G., Vandermeir, M. A., Paquay, R., de Brouwer, S., Porret, C. -A., Stergiopulos, N., Meister, J. -J., Verbeke, M., Van de Voorde, J., Lameire, N., De Clerck, N. M., De Schuytter, J., Tytgato, J., Buyse, G., Eggermont, J., Droogmans, G., Nilius, B., Daenens, P., Salomone, S., Feron, O., Dessy, C., Morel, N., Godfraind, T., Aloisi, A. M., Sacerdote, P., Lodi, L., Carli, G., Carobi, C., Garinei, G., Miniaci, U. C., Scotto, P., Sabatino, M., Sardo, P., Iurato, L., La Grutta, V., Bagni, M. A., Cecchi, G., Cecchini, E., Colomo, F., Garzella, P., Bottinelli, R., Harridge, S. D. H., Canepari, M., Reggiani, C., Reggiani, Saltin, Bambagioni, D., Fanò, G., Menchetti, G,, Danieli-Betto, P., Esposito, A., Betto, R., Megighian, A., Midrio, M., Betto, D. Danieli, Esposito, A., Megighian, A., Midrio, M., Orizio, C., Liberati, D., Locatelli, C., De Grandis, D., Veicsteinas, A., Angoli, D., Delia, D., Wanke, E., Bramucci, M., Miano, A., Quassinti, L., Maccari, E., Murri, O., Amici, D., Cibelli, G., Jüngling, S., Schoch, S., Gerdest, H. H., Thiel, G., Demori, I., Bottazzi, C., Voci, A., Fugassa, E., Barreca, A., Minuto, F., Gallo, G., Fulle, S., Belia, S., Menchetti, G., Cacchio, M., Fanò, G., Gastaldi, G., Laforenza, U., Ferrari, G., Rindi, G., Doni, M. G., Padoin, E., Residori, O., Cesaro, M., Toma, L., Rubini, A., Mutinelli, F, Paulesu, L., Romagnolie, R., Cintorino, M., Pippia, P., Meloni, M. A., Sciola, L., Spano, A., Cogoli-Greuter, M., Cogoli, A., Sardini, A., Mintenig, G. M., Valverde, M. A., Sepùlveda, F. V., Gill, D. R., Hyde, S. C., Higgins, C. F., McNaughton, P. A., Spena, A., Arcuri, M. T., Bonofiglio, S., Chimenti, R., Covello, C., De Cicco, T., Mazzulla, S., Martino, G., Tottene, A., Moretti, A., Pietrobon, D., Baccari, M. C., Calamai, F., Staderini, G., Cova, E., Marelli, R., Sommi, P., Ventura, U., Lombardi, A. M., Fabris, R., Pagano, C., Federspil, G., Vettor, R., Mancinelli, R., Tonali, P., Servidei, S., Romani, R., Tringali, A., Azzena, G. B., Mulè, F., Serio, R., Postorino, A., Pagano, C., Rizzato, M., Granzotto, M., Lombardi, A. M., Fabris, R., Vettor, R., Federspil, G., Sommi, P., Ricci, V., Romano, M., Ivey, K. J., Ventura, U., Vacca, G., Papillo, B., Mary, D. A. S. G., Battaglia, A., Grossini, E., Vacca, G., Papillo, B., Battaglia, A., Grossini, E., Accili, E. A., Redaelli, G., DiFrancesco, D., Antoniotti, S., Distasi, C., Lovisolo, D., Munaron, L., Bertaso, F., Assandri, R., Mazzanti, M., Bianchi, L., Arcangeli, A., Faravelli, L., Becchetti, A., Coronello, M., Mini, E., Francini, F., Olivotto, M., Wanke, E., Bigiani, A., Kim, D. -J., Roper, S. D., Carabelli, V., Lovallo, M., Magnelli, V., Zucker, H., Carbone, E., D’Angelo, E., Rossi, P., De Filippi, G., Taglietti, V., Faravelli, L., Bianchi, L., Arcangeli, A., Francini, F., Olivotto, M., Wanke, E., Francini, F., Bencini, C., Squecco, R., Guatteo, E., Bacci, A., Franceschetti, S., Avanzini, G., Wanke, E., Magnelli, V., Carbone, E., Mazzanti, M., Assandri, R., Ferroni, A., DiFrancesco, D., Navangione, A., Vellani, V., Rispoli, G., Peres, A., Centinaio, E., Giovannardi, S., Russo, G., Marcotti, W., Prigioni, I., Trequattrini, C., Harper, A. A., Petris, A., Franciolini, F., Zaza, A., Micheletti, M., Brioschi, A., Antonutto, G., Capelli, C., Girardis, M., Zamparo, P., di Prampero, P. E., Antonutto, G., Girardis, M., Tuniz, D., di Prampero, P. E., Filippi, G. M., Troiani, D., Grassi, B., Poole, D. C., Richardson, R. S., Knight, D. R., Erickson, B. K., Wagner, P. D., Aimi, B., Stilli, D., Gallo, P., Sgoifo, A., Lagrasta, C., Olivetti, G., Reali, N., Casti, A., Musso, E., Alloatti, G., Penna, C., Gallo, M. P., Levi, R. C., Fenoglio, I., Appendino, G., Gallo, P., Sgoifo, A., Medici, D., Aimi, B., Manghi, M., Stilli, D., Musso, E., Sgoifo, A., Pasini, E., Gallo, P., Aimi, B., Stilli, D., Ceconi, C., Musso, E., Baldissera, F., Cavallari, P., Locatelli, M., Bartesaghi, R., Gessi, T., Benfenati, F., Valtorta, F., Onofri, F., Poo, M., Greengard, P., Biagini, G., Sala, D., Viani§, P., Kozlov, A. V., Zini, I., Bravin, M., Tempia, F., Strata, P., Brescia, G., Di Benedetto, C., Corsi, P., Cangiano, G., Buttiglione, M., Ambrosini, M., Gennarini, G., Casadio, A., Levi, R. C., Montarolo, P. G., Cesare, P., Stoughton, R., McNaughton, P. A., D’Arcangelo, G., Dodt, H. U., Brancati, A., Zieglgänsberger, W., Errico, P., Ferraresi, A., Barmack, N. H., Pettorossi, V. E., Gasparini, S., D’Ambrosio, R., Janigro, D., DiFrancesco, D., Gritti, I., Marintti, M., Calcaterra, R., Freddi, R., Mancia, M., Imeri, I., Bianchi, S., Mancia, M., Lui, F., Gregory, K. M., Blanks, R. H. I., Giolli, R. A., Benassi, C., Corazza, R., Magherini, P. C., Bardoni, R., Belluzzi, O., Mancinelli, R., Manni, E., Azzena, G. B., Tringali, A., Romani, R., Diana, M., Fratta, W., Manzoni, D., Andre, P., Pompeiano, O., Mazzocchio, R., Rossi, A., Melis, F., Kitura, A., Caria, M. A., Asanuma, H., Melone, M, De Biasi, S, Minelli, A, Conti, F, Minelli, A, Karschin, C, DeBiasi, S, Brecha, N C, Conti, F, Monda, M., Amaro, S., Sullo, A., De Luca, B., Monda, M., Amaro, S., Sullo, A., De Luca, B., Pantò, M. R., Cicirata, F., Parenti, R., Serapide, M. F., Parenti, R., Wassef, M., Cicirata, F., Podda, M. V., Solinas, A., Chessa, G., Deriu, F., Mameli, O., Tolu, E., Pompeiano, O., Andre, P., Manzoni, D., Porro, C. A., Francescato, M. P., Cettolo, V., Diamond, M. E., Baraldi, P., Bazzocchi, M., Rivosecchi, R., Konnerth, A., Rossi, M. L., Martini, M., Pelucchi, B., Fesce, R., Santarelli, L., Schacher, S., Montarolo, P. G., Santarelli, R., Grassi, C., Valente, A., Nisticò, S., Bagetta, G., Azzena, G. B., Scuri, Rossana, Garcia-Gil, Mercedes, Mozzachiodi, Riccardo, Brunelli, Marcello, Stefani, G., Onofri, F., Vaccaro, P., Nielander, H. B., Benfenati, F., Tancredi, V., D’Antuono, M., Siniscalchi, A., Brancati, A., Avoli, M., Vellani, V., Navangione, A., Rispoli, G., Verzè, L., Buffo, A., Rossi, F., Oestreicher, A. B., Gispen, W. H., Strata, P., Zamboni, G., Amici, R., Jones, C. A., Perez, E., Domeniconi, R., Parmeggiani, P. L., Zoli, Michele, Le Novàre, Nicolas, Changeux, Jean -Pierre, Lafortuna, C. L., Reinach, E., Saibene, F., Scotto, P., Zocchi, L., Agostoni, E., and Cremaschi, D.

Published
1996
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12. Transnasal endoscopic surgery in selected nasal-ethmoidal cancer with suspected brain invasion: Indications, technique, and outcomes

Author

Mattavelli, D., Ferrari, M., Bolzoni Villaret, A., Schreiber, A., Rampinelli, V., Turri-Zanoni, M., Lancini, D., Taglietti, V., Accorona, R., Doglietto, Francesco, Battaglia, P., Castelnuovo, P., Nicolai, P., Doglietto F. (ORCID:0000-0002-7438-0734), Mattavelli, D., Ferrari, M., Bolzoni Villaret, A., Schreiber, A., Rampinelli, V., Turri-Zanoni, M., Lancini, D., Taglietti, V., Accorona, R., Doglietto, Francesco, Battaglia, P., Castelnuovo, P., Nicolai, P., and Doglietto F. (ORCID:0000-0002-7438-0734)

Abstract

Background: In nasal-ethmoidal malignancies, brain involvement is associated with dismal prognosis. Method: Patients undergoing endoscopic resection with transnasal craniectomy and subpial dissection (ERTC-SD) for brain-invading nasal-ethmoidal cancer between 2008 and 2016 were included. Complications were analyzed in all patients, whereas oncological outcomes only in patients with pathological brain invasion. The prognostic impact of previous treatments, brain edema, and histology was assessed. Hospitalization ratio was calculated. Results: Nineteen patients received ERTC-SD and 11 had pathological-proven brain invasion. Histologies were 6 olfactory neuroblastomas (ONB), 3 neuroendocrine carcinomas, and 2 intestinal-type adenocarcinomas. Mean follow-up was 21.9 months. Three-year overall, local recurrence-free, and distance recurrence-free survivals were 65.5%, 81.8%, and 68.2%, respectively. Overall and distant recurrence-free survivals were significantly better in patients with ONB (P = 0.032 and P = 0.013, respectively). Hospitalization ratio was 4.1%. Complication rate was 10.5%. Conclusion: In selected nasal-ethmoidal tumors with brain invasion, ERTC-SD can provide good local control, satisfactory survival, and limited morbidity.

Published
2019

13. AMPK in the central nervous system: physiological roles and pathological implications

Author

Rosso P, Fioramonti M, Fracassi A, Marangoni M, Taglietti V, Siteni S, and Segatto M

Subjects
AMPK, tumor, lcsh:Biology (General), brain, neurodegeneration, stroke, lcsh:QH301-705.5
Abstract

Pamela Rosso,1,2,* Marco Fioramonti,3,* Anna Fracassi,2 Martina Marangoni,4 Valentina Taglietti,5 Silvia Siteni,2,6 Marco Segatto5 1Institute of Cell Biology and Neurobiology, National Research Council (CNR), 2Department of Sciences, University of Rome “Roma Tre”, 3Laboratory of Translational Oncology, University Campus Bio-Medico of Rome, 4Medical Genetics Unit, University Hospital of Rome “Tor Vergata”, Rome, 5Department of Biosciences, University of Milan, Milan, 6Department of Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy *These authors contributed equally to this work Abstract: 5′ AMP-activated protein kinase (AMPK) is considered the master metabolic regulator in all eukaryotes, as it maintains cellular energy homeostasis in a variety of tissues, including the brain. In humans, alterations in AMPK activity can lead to a wide spectrum of metabolic disorders. The relevance of this protein kinase in the pathogenesis of diabetes and metabolic syndrome is now well established. On the contrary, correlations between AMPK and brain physiopathology are still poorly characterized. The aim of this review is to summarize and discuss the current knowledge about the prospective involvement of AMPK in the onset and the progression of different neurological diseases. Keywords: AMPK, brain, neurodegeneration, stroke, tumor, autophagy

Published
2016

23. Cardiac microvascular endothelial cells express a functional Ca 2+-sensing receptor

Author

BERRA ROMANI, R, Raqeeb, A, Laforenza, U, Scaffino, Mf, Moccia, F, AVELINO CRUZ JE, Oldani, A, Coltrini, Daniela, Milesi, V, Taglietti, V, and Tanzi, F.

Subjects
Ca2+-sensing receptor, Na+/Ca2+ exchanger, Phospholipase C, Cardiac microvascular endothelial cells, Inositol 1,4,5-trisphosphate, Cardiac function, Química, Extracellular Ca2+, Fura-2/AM, Vascular tone
Abstract

The mechanism whereby extracellular Ca2+ exerts the endothelium-dependent control of vascular tone is still unclear. In this study, we assessed whether cardiac microvascular endothelial cells (CMEC) express a functional extracellular Ca2+-sensing receptor (CaSR) using a variety of techniques. CaSR mRNA was detected using RT-PCR, and CaSR protein was identified by immunocytochemical analysis. In order to assess the functionality of the receptor, CMEC were loaded with the Ca2+-sensitive fluorochrome, Fura-2/AM. A number of CaSR agonists, such as spermine, Gd 3+, La3+ and neomycin, elicited a heterogeneous intracellular Ca2+ signal, which was abolished by disruption of inositol 1,4,5-trisphosphate (InsP3) signaling and by depletion of intracellular stores with cyclopiazonic acid. The inhibition of the Na +/Ca2+ exchanger upon substitution of extracellular Na+ unmasked the Ca2+ signal triggered by an increase in extracellular Ca2+ levels. Finally, aromatic amino acids, which function as allosteric activators of CaSR, potentiated the Ca2+ response to the CaSR agonist La3+. These data provide evidence that CMEC express CaSR, which is able to respond to physiological agonists by mobilizing Ca2+ from intracellular InsP3-sensitive stores., Facultad de Ciencias Exactas

Published
2008

24. Caveolin-1 expression and membrane cholesterol content modulate N-type calcium channel activity in NG108-15 cells

Author

Toselli, M, Biella, G, Taglietti, V, Cazzaniga, E, Parenti, M, PARENTI, MARCO DOMENICO, Toselli, M, Biella, G, Taglietti, V, Cazzaniga, E, Parenti, M, and PARENTI, MARCO DOMENICO

Abstract

Caveolins are the main structural proteins of glycolipid/cholesterol-rich plasmalemmal invaginations, termed caveolae. In addition, caveolin-1 isoform takes part in membrane remodelling as it binds and transports newly synthesized cholesterol from endoplasmic reticulum to the plasma membrane. Caveolin-1 is expressed in many cell types, including hippocampal neurons, where an abundant SNAP25-caveolin-1 complex is detected after induction of persistent synaptic potentiation. To ascertain whether caveolin-1 influences neuronal voltage-gated Ca2+ channel basal activity, we stably expressed caveolin-1 into transfected neuroblastoma x glioma NG108-15 hybrid cells [cav1(+) clone] that lack endogenous caveolins but express N-type Ca2+ channels upon cAMP-induced neuronal differentiation. Whole-cell patch-clamp recordings of cav1(+) cells demonstrated that N-type current density was reduced in size by approximately 70% without any significant change in the time course of activation and inactivation and voltage dependence. Moreover, the cav1(+) clone exhibited a significantly increased proportion of membrane cholesterol compared to wild-type NG108-15 cells. To gain insight into the mechanism underlying caveolin-1 lowering of N-current density, and more precisely to test whether this was indirectly caused by caveolin-1-induced enhancement of membrane cholesterol, we compared single N-type channel activities in cav1(+) clone and wild-type NG108-15 cells enriched with cholesterol after exposure to a methyl-beta-cyclodextrin-cholesterol complex. A lower Ca2+ channel activity was recorded from cell-attached patches of both cell types, thus supporting the view that the increased proportion of membrane cholesterol is ultimately responsible for the effect. This is due to a reduction in the probability of channel opening caused by a significant decrease of channel mean open time and by an increase of the frequency of null sweeps.

Published
2005

38. Cu2+, Co2+, and Mn2+ modify the gating kinetics of high-voltage-activated Ca2+ channels in rat palaeocortical neurons.

Author

Castelli, L., Tanzi, F., Taglietti, V., and Magistretti, J.

Subjects
CATIONS, CALCIUM, COPPER, COBALT, MANGANESE, PATCH-clamp techniques (Electrophysiology), BIOLOGICAL transport, NEURAL physiology, ANIMAL experimentation, BARIUM, CELLULAR signal transduction, CYTOLOGICAL techniques, DYNAMICS, NEURONS, RATS, IN vitro studies, PHYSIOLOGY
Abstract

The effects of three divalent metal cations (Mn2+, Co2+, and Cu2+) on high-voltage-activated (HVA) Ca2+ currents were studied in acutely dissociated pyramidal neurons of rat piriform cortex using the patch-clamp technique. Cu2+, Mn2+, and Co2+ blocked HVA currents conducted by Ba2+ (IBa) with IC50 of 920 nM, 58 µM, and 65 µM, respectively. Additionally, after application of non-saturating concentrations of the three cations, residual currents activated with substantially slower kinetics than control IBa. As a consequence, the current fraction abolished by the blocking cations typically displayed, in its early phase, an unusually fast-decaying transient. The latter phenomenon turned out to be a subtraction artifact, since none of the pharmacological components (L-, N-, P/Q-, and R-type) that constitute the total HVA currents under study showed a similarly fast early decay: hence, the slow activation kinetics of residual currents was not due to the preferential inhibition of a fast-activating/inactivating component, but rather to a true slowing effect of the blocker cations. The percent IBa-amplitude inhibition caused by Mn2+, Co2+, and Cu2+ was voltage-independent over the whole potential range explored (up to +30 mV), hence the slowing of IBa activation kinetics was not due to a mechanism of voltage- and time-dependent relief from block. Moreover, Mn2+, Co2+, and Cu2+ significantly reduced IBa deactivation speed upon repolarization, which also is not compatible with a depolarization-dependent unblocking mechanism. The above results show that 1) Cu2+ is a particularly potent HVA Ca2+-channel blocker in rat palaeocortical neurons; and 2) Mn2+, Co2+, and Cu2+, besides exerting a blocking action on HVA Ca2+-channels, also modify Ca2+-current activation and deactivation kinetics, most probably by directly interfering with channel-state transitions. [ABSTRACT FROM AUTHOR]

Published
2003
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40. P2Y1and P2Y2Receptor-Operated Ca2+Signals in Primary Cultures of Cardiac Microvascular Endothelial Cells

Author

Moccia, F., Baruffi, S., Spaggiari, S., Coltrini, D., Berra-Romani, R., Signorelli, S., Castelli, L., Taglietti, V., and Tanzi, F.

Abstract

Intracellular Ca2+signals elicited by nucleotide agonists were investigated in primary cultures of rat cardiac microvascular endothelial cells using the fura-2 technique. UTP increased the intracellular [Ca2+] in 94% of the cells, whereas 2MeSATP was active in 32%. The rank order of potency was ATP = UTP > 2MeSATP and the maximal response to 2MeSATP was lower compared to UTP and ATP. ATP and UTP showed strong homologous and heterologous desensitization. ATP fully inhibited the 2MeSATP response, while UTP abolished 2MeSATP-elicited transients in 25% of cells. 2MeSATP did not desensitize the UTP or ATP response. Adenosine 2′,5′-diphosphate inhibited the response to 2MeSATP, while it did not modify the response to ATP and UTP. 2MeSATP was more sensitive to suramin than UTP and ATP. These results indicate that P2Y1and P2Y2receptors may be coexpressed in CMEC. Nucleotide-induced Ca2+signals lacked a sustained plateau and were almost independent from extracellular Ca2+. ATP and UTP elicited Ca2+transients longer than 2MeSATP-evoked transients. The kinetics of Ca2+responses was not affected by bath solution stirring or ectonucleotidase inhibition. Furthermore, the nonhydrolyzable ATP analogue AMP-PNP induced Ca2+signals similar to those elicited by ATP and UTP. These results suggest that the distinct kinetics of nucleotide-evoked Ca2+responses do not depend on the activity of ectonucleotidases or ATP autocrine stimulation. The possibility that Ca2+signals with different time courses may modulate different cellular responses is discussed.

Published
2001
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41. A study of stretch‐activated channels in the membrane of frog oocytes: interactions with Ca2+ ions.

Author

Taglietti, V and Toselli, M

Abstract

1. We have carried out patch‐clamp measurements on a cationic channel in the plasma membrane of the frog oocyte, which can be specifically activated by membrane stretch. The kinetics of this channel also display a distinct dependence upon membrane potential, the probability of the channel being open increasing with membrane depolarization. 2. When the patch‐clamp pipette filling solution was standard Ringer solution, the single‐channel current‐voltage (I‐V) relationship was linear, the elementary conductance being 38 pS and the reversal potential +7 mV, suggesting very poor selectivity of the channel for the various cations. 3. The I‐V relationship was highly non‐linear having a strong inward‐going rectification when Ca2+‐free solutions were used to fill the patch pipette. These solutions also resulted in a selective, inward cationic permeability through the membrane, with K+ being more permeable than Na+ greater than Li+ greater than Ba2+ greater than Ca2+. 4. Though permeant through the stretch‐activated channel, Ca2+ inhibited in a concentration‐dependent manner the currents carried by other cations. La3+ (0.1 mM) was also an effective channel blocker. 5. The inward current carried by individual cations at a given membrane potential increased with increasing external cation concentration up to a saturating level, this level being maximal for K+ and minimal for Ca2+. Also the half‐saturating concentration was maximal for K+ and minimal for Ca2+ at all membrane potentials. 6. In the presence of a constant Ca2+ concentration (50 microM) increasing [K+] did not change the absolute level at which the current saturated; however the half‐saturating K+ concentration was greatly increased, indicating competitive inhibition between Ca2+ and K+ for the same site. 7. The data are consistent with a model based on Eyring rate theory for current conduction through ionic channels, in which we assume that the ions capable of entering the channel compete for a binding site that they must first occupy before proceeding on. The possible energy profile of the stretch‐activated channel was defined by optimizing the model parameters to obtain the best fit of the experimental data. Ca2+ was found to have a smaller dissociation constant and much longer occupancy time than Na+ or K+, thus accounting for its lower permeability and inhibitory effect on current conduction by other cations through the stretch‐activatable channel.

Published
1988
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42. Synaptic activation of Ca2+ action potentials in immature rat cerebellar granule cells in situ.

Author

D'Angelo, E, De Filippi, G, Rossi, P, and Taglietti, V

Abstract

Although numerous Ca2+ channels have been identified in cerebellar granule cells, their role in regulating excitability remained unclear. We therefore investigated the excitable response in granule cells using whole cell patch-clamp recordings in acute rat cerebellar slices throughout the time of development (P4-P21, n = 183), with the aim of identifying the role of Ca2+ channels and their activation mechanism. After depolarizing current injection, 46% of granule cells showed Ca2+ action potentials, whereas repetitive Na+ spikes were observed in an increasing proportion of granule cells from P4 to P21. Because Ca2+ action potentials were no longer observed after P21, they characterized an immature granule cell functional stage. Ca2+ action potentials consisted of an intermediate-threshold spike (ITS) activating at -60/-50 mV and sensitive to voltage inactivation and of a high-threshold spike (HTS), activating at above -30 mV and resistant to voltage inactivation. Both ITS and HTS comprised transient and protracted Ca2+ channel-dependent depolarizations. The Ca2+ action potentials could be activated synaptically by excitatory postsynaptic potentials, which were significantly slower and had a proportionately greater N-methyl-D-aspartate (NMDA) receptor-mediated component than those recorded in cells with fast repetitive Na+ spikes. The NMDA receptor current, by providing a sustained and regenerative current injection, was critical for activating the ITS, which was not self-regenerative. Moreover, NMDA receptors determined temporal summation of impulses during repetitive mossy fiber transmission, raising membrane potential into the range required for generating protracted Ca2+ channel-dependent depolarizations. The nature of Ca2+ action potentials was considered further using selective ion channel blockers. N-, L-, and P-type Ca2+ channels generated protracted depolarizations, whereas the ITS and HTS transient phase was generated by putative R-type channels (R(ITS) and R(HTS), respectively). R(HTS) channels had a higher activation threshold and were more resistant to voltage inactivation than R(ITS) channels. At a mature stage, most of the Ca2+-dependent effects depended on the N-type current, which promoted spike repolarization and regulated the Na+-dependent discharge frequency. These observations relate Ca2+ channel types with specific neuronal excitable properties and developmental states in situ. Synaptic NMDA receptor-dependent activation of Ca2+ action potentials provides a sophisticated mechanism for Ca2+ signaling, which might be involved in granule cell development and plasticity.

Published
1997

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