Communication between neuronal and non-neuronal is called volume transmission when the released neurotransmitter (NT) acts via diffusion and affects several target cells. Both the neurosecretory and postsynaptic cell responses are linked to [Ca2+]i elevations. In the present thesis the role of pre-and postsynaptic Ca2+ elevations has been investigated in the reconstituted "synapse" model comprised of NGF-differentiated PC12 and HEL cells as well as in SH-SY5Y neuroblastoma cells. In PC12 cells, both 70mM K+ and nicotine triggered NT release, which could be detected as a secondary [Ca2+]i increase in surrounding HEL cells. Both secretagogues shared the same voltage-dependent Ca2+ influx pathway as judged from the pharmacological profile blockers of voltage-gated Ca2+ channels. The coupling of electrical responses to the activation of Ca2+ signaling via muscarinic receptors in SH-SY5Y cells was also studied. These data revealed that depolarization caused a considerable potentiation of the muscarinic Ca2+ response. The potentiated Ca2+ increase was mainly dependent on the enhanced Ca2+ influx and to a lesser extent on [Ca2+]i release from intracellular stores. A phospholipase C (PLC) activator, m-3M3FBS was used to further study the role of G-protein coupled receptor (GPCR)-coupled Ca2+ signaling. However, it was found that m-3M3FBS instead triggered [Ca2+]i elevations independently of PLC activation. In conclusion, the results indicate that the magnitude of NT release from PC12 cells is sufficient to cause a robust activation of neighboring target cells. Postsynaptic muscarinic signaling is amplified due to integration of electrical excitation and GPCR signaling. The PLC activator, m-3M3FBS is not suitable for studies of PLC-mediated signals in intact cells.

The objective of this thesis was to relate and link the physiological responses of the cells to the electrical responses or output obtained from the TSM acoustic wave sensor. In particular, the device was applied to the study of immortalized murine hypothalamic neurons (mHypoE-38 and -46 cell models) under a variety of conditions and stimuli. Cellular studies which lead to the production of detectable neuronal responses include neuronal deposition, adhesion and proliferation, alteration in the extent of specific cell-surface interactions, actin filament and microtubule cytoskeletal disruptions, effects of cell depolarization, solution tonicity, inhibition of the Na+-K+ pump via ouabain, effects of neuronal synchronization and the effects ligand-receptor interaction (glucagon). In addition, the introduction of drugs, neurotrophic factors (forskolin and beterferon), toxicity agents (NaOH, EtOH) and TiO2 nanoparticles were similarly investigated. A preliminary study conducted with mouse embryonic stem cells showed that not all cell lines are suitable for investigation with the TSM sensor at the current stage of sensor development. It has been found that control studies conducted with water as the solvent and the bare sensor substrate is insufficient to model the behavior of the sensor in the absence of cells. When biological buffers are used in addition to protein coatings the sensor responses are altered in magnitude and direction. To analyze the full range of cellular changes observed on the TSM sensor, the full impedance spectrum is required. As such in this thesis, the series and parallel resonant frequencies, the motional resistance, the maximum phase of the impedance and the static capacitance (fs, fp, Rm, θmax and Co were used to characterize the cellular responses observed. In the presence of cells fs shifts are largely influenced by the damping of the TSM resonator. The formation of cell-surface interactions and hence the increase in coupling and acoustic energy dissipation can be modeled as an additional resistor in the BVD model. Further sensor and cellular changes can be obtained by negating the effects of damping from fs with the use of Rm and θmax.

The objective of this thesis was to relate and link the physiological responses of the cells to the electrical responses or output obtained from the TSM acoustic wave sensor. In particular, the device was applied to the study of immortalized murine hypothalamic neurons (mHypoE-38 and -46 cell models) under a variety of conditions and stimuli. Cellular studies which lead to the production of detectable neuronal responses include neuronal deposition, adhesion and proliferation, alteration in the extent of specific cell-surface interactions, actin filament and microtubule cytoskeletal disruptions, effects of cell depolarization, solution tonicity, inhibition of the Na+-K+ pump via ouabain, effects of neuronal synchronization and the effects ligand-receptor interaction (glucagon). In addition, the introduction of drugs, neurotrophic factors (forskolin and beterferon), toxicity agents (NaOH, EtOH) and TiO2 nanoparticles were similarly investigated. A preliminary study conducted with mouse embryonic stem cells showed that not all cell lines are suitable for investigation with the TSM sensor at the current stage of sensor development. It has been found that control studies conducted with water as the solvent and the bare sensor substrate is insufficient to model the behavior of the sensor in the absence of cells. When biological buffers are used in addition to protein coatings the sensor responses are altered in magnitude and direction. To analyze the full range of cellular changes observed on the TSM sensor, the full impedance spectrum is required. As such in this thesis, the series and parallel resonant frequencies, the motional resistance, the maximum phase of the impedance and the static capacitance (fs, fp, Rm, θmax and Co were used to characterize the cellular responses observed. In the presence of cells fs shifts are largely influenced by the damping of the TSM resonator. The formation of cell-surface interactions and hence the increase in coupling and acoustic energy dissipation can be modeled as an additional resistor in the BVD model. Further sensor and cellular changes can be obtained by negating the effects of damping from fs with the use of Rm and θmax.

L'épilepsie est l’un des désordres neurologiques les plus courants; environ 1% de la population mondiale en est atteinte. Elle affecte le fonctionnement des neurones qui s'exprime par une survenue de décharges rapides, appelées crises.Les crises peuvent parfois résister aux médicaments antiépileptiques. Cet état de crise, nommé refractory status epilepticus (RSE), se définit par une survenue des décharges de façon continue, qui sont difficiles à arrêter. Malheureusement, un patient en état RSE risque même de mourir.Le dysfonctionnement des neurones peut parfois se propager lentement vers une dépression corticale envahissante, qui se caractérise par une dépolarisation lente des neurones entraînant une baisse transitoire de l’activité cérébrale.Les mécanismes qui initient ces activités pathologiques restent encore mal connus. Mettant en œuvre une approche mathématique, nous présentons une analyse qualitative d’un modèle dit Epileptor, qui reproduit l’activité épileptique, et décrivons l’évolution temporelle de la crise jusqu’au moment où la personne revient à la normale. La transition vers l’état normal est interprétée comme une bifurcation. Nous démontrons qu’il en existe plusieurs types en variant certains paramètres du modèle, permettant ainsi de classer les crises.Une caractérisation de ces activités est nécessaire pour s’en échapper. Pour ce faire, nous explorons un espace des paramètres permettant de conclure que ces activités coexistent dans le cerveau et surviennent de plusieurs façons. Cet espace des paramètres propose plusieurs voies, qui sont validées expérimentalement, pour éviter ces activités pathologiques et retourner à la normale, d’où son importance. / Epilepsy is one of the most common serious neurological disorders affecting about 1% of the population in the world. It is a condition of the nervous system in which neuronal populations manifest as abnormal excessive discharges, called seizures.On rare occasions, a seizure follows another in a series without recovery, and does not respondto antiepileptic drugs. This state of continuous seizure activity is called refractory status epilepticus, which are difficult to treat. Patients suffering from this state are unfortunately at an increased risk of death.The neuronal dysfunction can sometimes spread slowly towards a spreading depression, which corresponds to a slowly propagating depolarization wave (or depolarization block DB) in neuronal networks, followed by a shut down of brain activity.The mechanisms underlying the genesis of these activities remain unknown. Using a mathematical approach, we present a qualitative analysis of a so-called Epileptor model, which generate epileptic dynamics, and describe how seizures evolve toward termination. The transition to the normal state occurs through a bifurcation. We demonstrate that many types of the bifurcation exist, depending on the values of some parameters. As a consequence, we can classify seizures.To escape from these activities, a characterization is going to be necessary. To this, we explore a parameter space of the model which demonstrate that these activities coexist in the brain, and under some ways. In addition, the parameter space can provide pathways to switch between these activities. Interestingly, we could propose how to return to the ’normal’ brain activity.

Ametistas naturais brasileiras foram estudadas através das técnicas de Absorção Óptica (AO), Ressonância Paramagnética Eletrônica (RPE) e Corrente de Despolarização Termicamente Estimulada (CDTE).O espectro de AO apresentou três picos principais na região espectral do visível (10500, 18600 e 28200cm POT.-1) e um enorme pico na região do ultravioleta (45000cm POT.-1) atribuídos ao ferro em diferentes estados de valência. A presença de centros OH POT.- foi observada na região do infravermelho através das bandas em 3440 e 3580cm POT.-1. O espectro de RPE, operando na banda X, exibe um conjunto de linhas centrado em 2000G, um pico intenso em 3000G e quatro picos pequenos em 4000, 5000, 6000 e 7000G, quando o campo magnético encontra-se paralelo a um dos eixos cristalograficamente equivalentes. Quando o campo magnético encontra-se paralelo ao eixo c do cristal, o espectro de RPE revela um conjunto de linhas centrado em 2000G, dois picos intensos próximos a 5000G e um pico pequeno em 6800G. Amostras em pó apresentam uma banda larga centrada em 3400G. Tratamentos térmicos mostram uma redução gradativa desta banda com o aumento do tempo de tratamento térmico e uma redução mais rápida para temperaturas maiores. Sabe-se que os centros de cor nas ametistas são produzidos pela ação de radiação ionizante natural sobre os centros precursores que surgem da substituição do Si POT.4+ pelo Fe POT.3+ na estrutura do quartzo-alfa. Esses centros de Fe POT.3+ não se distribuem igualmente entre os sítios equivalentes no cristal natural e são responsáveis pelas características dominantes do espectro de RPE. O espectro de CDTE obtido da polarização de uma amostra em 1000V apresenta uma banda em 215K, que vem a ser a composição de três bandas de menor intensidade (185, 200 e 214K) e uma banda única em 260K. Foi confirmado o caráter dipolar dessas bandas. Tratamentos térmicos efetuados a diferentes temperaturas mostram ) um decaimento de área total e uma redução da intensidade das bandas mais acentuadas para temperaturas maiores. Iluminação ultravioleta restaura parcialmente o espectro de CDTE e demonstra o crescimento de uma banda na região da temperatura ambiente. Devido ao comportamento semelhante dos espectros de CDTE e de RPE, o sendo Fe POT.3+ um elemento presente em grande quantidade nas amostras estudadas, acredita-se que o centro de dipolo responsável pelas bandas de CDTE observadas, seja do Fe POT.3+ substituindo um Si POT.4+ próximo a um O POT.- ou a um OH POT.-, e que as diferentes posições dos picos devem-se à população desigual do Fe POT.3+ substitucional nos sítios cristalograficamente equivalentes do cristal. / Brazilian natural amethyst samples have been studied through Optical Absorption (AO), Electron Paramagnetic Resonance (EPR) and Thermally Stimulated Depolarization Current (TSDC) Techniques.The AO spectrum shows three main peaks in the visible region (10500, 18600 e 28200cm POT.-1) and a huge peak in the ultraviolet region (45000cm POT.-1). All these peaks were attributed to iron in different valence states. The presence of centros OH POT.- centres have been observed through the bands at 3440 e 3580cm POT.-1in the infrared.The EPR spectrum shows a set of lines centered at 2000G, an intense peak at 3000G and four small peaks at 4000, 5000, 6000 and 7000G, when the magnetic field is parallel to one of crystallographically equivalents sites. When the magnetic field is parallel to the crystal c-axis, the EPR spectrum shows a set of lines centered at 2000G, two high peaks near 5000G and a small peak at 6800G. Powder samples presents a broad band centered in 3400G. Thermal treatments reduce this band for increasing thermal treatments time intervals. The reduction increases for high temperatures. It is well known that colour centres in amethysts are produced after natural ionizing radiation and that the centres are provided with the substitution of Fe POT.3+ for Si POT.4+ in quartzo-alfa structure. The Fe POT.3+ centres are not equally distributed among the equivalent sites of the natural crystal and are responsible for the dominant features of the EPR spectra. The obtained TSDC spectrum for polarization at 1000V shows a broad band at 215K, resulting from the superposition of three bands at 185, 200 and 214k and another band at 260K. The dipole origin of these bands has been confirmed. Thermal treatments at different temperatures produce a decay of the total area and a reduction of the bands intensities. Thermal reduction increases for higher temperatures. Ultraviolet illumination partially restores the TSDC spectrum. A new band appears at room temperature. Due to the similar behavior of the TSDC and EPR spectra and taking into account that the Fe POT.3+ is the most prominent impurity in the studied samples, we believe that the dipoles are substitutional Fe POT.3+ near O POT.- or an OH POT.- and that the different position of the peaks, very near, but not the same, are in crystallographically equivalent sites.

The typical construction of a stator coil includes the use of end corona protection (ECP)coating, which is made of semi-conductive materials like silicon carbide (SiC). Thepurpose of ECP is to smooth the electric stress distribution near the slot exit, limitingthe electric field and partial discharge (PD) activity within the insulation system. Thisthesis investigates how ECP affects the dielectric response of a stator coil in highvoltagemeasurements, both in the time-domain and frequency-domain. It also studieshow well time-domain results transformed to the frequency-domain correspond to directmeasurements. As a further point, the effect of the ECP on PD activity was demonstrated.Measurements of dielectric response and PD were made on new coil-halves producedin the usual way in a production run for a motor. The results show that applying theECP design significantly reduces the PD activity and increases the inception voltage. Inaddition, the dielectric response of the coil with ECP tape has shown to have a nonlinearvoltage dependent characteristic due to the presence of ECP. As the voltage goes higher,this causes a shift of the loss peak toward higher frequency. A distributed-element modelof the end section of a stator coil was used to model the nonlinear effect due to ECP, andits results are compared to the measured results. Lastly, FEM simulation of a stator coilend section is presented, showing the contribution of ECP tape in evenly distributing theelectric stress near the slot exit. / Den typiska konstruktionen av en statorhärva använder ändglimmskydd (ECP), somär tillverkad av halvledande material som kiselkarbid (SiC). Syftet med ECP är attjämna ut det elektriska fältet vidövergången från spåret tilländlindningen, för attundvika högpåkänning och partiell urladdningsaktivitet (PD). Arbetet som presenteras här undersöker hur ECP påverkar den dielektriska responsen hos en statorspole, vid tidsdomänoch frekvensdomänmätningar vid höga spänningar. Den studerar också hur väl tidsdomänresultat som omvandlas till frekvensdomänen motsvarar direkta mätningar. Som en annan punkt visades ECP:s inverkan på PD-aktivitet. Mätningar av dielektrisk respons och PD gjordes på nya statorhärvor som tillverkades för en stor motor. Resultaten visar att tillämpningen av ECP-konstruktionen avsevärt minskar PD-aktiviteten och ökar inceptionsspänningen. Dessutom har spolens dielektriska respons med ECP-tejp visat sig ha en ickelinjär spänningsberoende egenskap på grund av närvaron av ECP. Ö kad spänning orsakar en förskjutning av förlusttoppen mot högre frekvens. En modell för ECP användeseteendet, och dess resultat jämförs med mätningarna.utligen presenteras FEM-simulering som visar hur ECP gör fältet jämnare.

Electronic energy transfer has been investigated in pure donor systems by means of computer simulations. Calculated properties were the probability that the initially excited donor is excited at a time t after the excitation, Gs(t), the mean square displacement of the excitation and different fluorescence observables. For three dimensional systems the results obtained by Monte Carlo simulations were compared to the so-called GAF-theory {Gouchanour,C. R., Andersen, H. C. and Fayer, M. D., J. Chem. Phys. 81, 4380 (1984)}, and the agreement was found to be good. Anisotropic systems, i.e. mono-, bi- and multilayer systems, were compared to the two-particle model {Baumann,J. and Fayer, M. D., J. Chem. Phys. 85, 4087 (1986)}. The agreement between the Gs(t) calculated from the tp- model and the Monte Carlo simulations were good for all systems investigated. However, the agreement between the fluorescence observables obtained by MC and the tp-model were in general poor. A much better agreement was found when a phenomenological approach was used for calculating the fluorescence depolarization ratios. Three dimensional systems where the donors are rotating on the same time scale as the energy transfer takes place have also been studied and compared to analytical theories. The Molecular Dynamics simulations of decapeptide H142 shows that simulations in a continuum with a relative permeability do not provide a reliable alternative to simulations with explicit solvent molecules. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1991, härtill 5 uppsatser</p> / digitalisering@umu

Esta dissertação poderia ser dividida em duas partes, sem que houvesse prejuízo para o seu entedimento: uma tratando do topázio natural (Al IND.2 SiO IND.4[F, OH] IND.2) e outra, a respeito dos vidros silicatos tipo soda-lime (SiO IND.2+CaO+Na IND.2 O). Em ambas se procura contribuir para o estudo de defeitos com algumas técnicas experimentais, mais enfaticamente as correntes de despolarização termicamente estimuladas (CDTE). Com relação ao topázio, há diversos estudos tratando de sua termoluminescência (TL) e de possíveis aplicações no que tange ao seu emprego como dosímetro termoluminescente. Procuramos complementar esses resultados com medidas de CDTE, técnica que ainda não havia sido utilizada para este material. Localizamos no topázio três bandas de CDTE, porém os resultados não são conclusivos no que se refere às origens dessas bandas. Em parte porque temos consciência de que os resultados variam bastante quando se estudam amostras naturais, com composições que variam dentro de um mesmo pedaço de cristal. No que diz respeito aos vidros soda-lime, o estudo foi mais abrangente. Há várias trabalhos no sentido de se conhecer melhor os efeitos causados pela irradiação de vidros silicatos. Acredita-se que o sódio desempenhe um papel fundamental nas principais mudanças processadas nesse material após irradiação gama. Assim, este estudo procurou comparar os resultados de TL e CDTE, além de absorção óptica, de vidros soda-lime com diferentes concentrações de Na POT.+ e K POT.+. Ao que tudo indica os processos responsáveis pela TL e CDTE dependem da relação entre as concentrações desses íons. Verificaram-se também variações com a taxa de dose, e os efeitos de tratamentos térmicos para situações onde um ou outro íon prevalece. / This work could be split in two different parts without impairment understanding. One of them, on natural topaz (Al2SiOdF,OH] 2) and the other on soda-lime silicate (SLS) glasses (Si02 + CaO + Na20) . In both of them we intend to contribute with more information on their defect composition, using some experimental techniques, especially the so called thermally stimulated depolarization currents (TSDC) . There are many surveys on topaz thermoluminescence (TL) and the possibility of its use as a TL dosimeter. So, one of the purposes of this study was to make a contribution with a technique not used so far with such material. We have detected three TSDC peaks. The results are not conclusive about the origin of those peaks, in part because we are dealing with a natural material whose composition can vary even within the same piece of crystal. As the SLS glasses, the study was more comprehensive. There are plenty of papers on irradiation effects in silicate glasses and attempts to understand the mechanisms responsible for them. It is believed that sodium plays a fundamental role in the main modifications caused by gamma irradiation of these glasses. In addition, this study attempts to compare the TL and TSDC results in SLS glasses with different concentrations of Na+ and K+. From our observations, the processes responsible for both TL and TSCD peaks depend on the relative concentrations of those ions. Furthermore, variations on the signals were also noticed; depending on the irradiation rate and on the thermal treatments performed, in samples where one or another ion prevails.

Esta dissertação poderia ser dividida em duas partes, sem que houvesse prejuízo para o seu entedimento: uma tratando do topázio natural (Al IND.2 SiO IND.4[F, OH] IND.2) e outra, a respeito dos vidros silicatos tipo soda-lime (SiO IND.2+CaO+Na IND.2 O). Em ambas se procura contribuir para o estudo de defeitos com algumas técnicas experimentais, mais enfaticamente as correntes de despolarização termicamente estimuladas (CDTE). Com relação ao topázio, há diversos estudos tratando de sua termoluminescência (TL) e de possíveis aplicações no que tange ao seu emprego como dosímetro termoluminescente. Procuramos complementar esses resultados com medidas de CDTE, técnica que ainda não havia sido utilizada para este material. Localizamos no topázio três bandas de CDTE, porém os resultados não são conclusivos no que se refere às origens dessas bandas. Em parte porque temos consciência de que os resultados variam bastante quando se estudam amostras naturais, com composições que variam dentro de um mesmo pedaço de cristal. No que diz respeito aos vidros soda-lime, o estudo foi mais abrangente. Há várias trabalhos no sentido de se conhecer melhor os efeitos causados pela irradiação de vidros silicatos. Acredita-se que o sódio desempenhe um papel fundamental nas principais mudanças processadas nesse material após irradiação gama. Assim, este estudo procurou comparar os resultados de TL e CDTE, além de absorção óptica, de vidros soda-lime com diferentes concentrações de Na POT.+ e K POT.+. Ao que tudo indica os processos responsáveis pela TL e CDTE dependem da relação entre as concentrações desses íons. Verificaram-se também variações com a taxa de dose, e os efeitos de tratamentos térmicos para situações onde um ou outro íon prevalece. / This work could be split in two different parts without impairment understanding. One of them, on natural topaz (Al2SiOdF,OH] 2) and the other on soda-lime silicate (SLS) glasses (Si02 + CaO + Na20) . In both of them we intend to contribute with more information on their defect composition, using some experimental techniques, especially the so called thermally stimulated depolarization currents (TSDC) . There are many surveys on topaz thermoluminescence (TL) and the possibility of its use as a TL dosimeter. So, one of the purposes of this study was to make a contribution with a technique not used so far with such material. We have detected three TSDC peaks. The results are not conclusive about the origin of those peaks, in part because we are dealing with a natural material whose composition can vary even within the same piece of crystal. As the SLS glasses, the study was more comprehensive. There are plenty of papers on irradiation effects in silicate glasses and attempts to understand the mechanisms responsible for them. It is believed that sodium plays a fundamental role in the main modifications caused by gamma irradiation of these glasses. In addition, this study attempts to compare the TL and TSDC results in SLS glasses with different concentrations of Na+ and K+. From our observations, the processes responsible for both TL and TSCD peaks depend on the relative concentrations of those ions. Furthermore, variations on the signals were also noticed; depending on the irradiation rate and on the thermal treatments performed, in samples where one or another ion prevails.

L’automatisme cardiaque est généré par un mécanisme fondamental partiellement compris et controversé, initié par des cardiomyocytes spécialisés dans le nœud sino-atrial (NSA). Ces cellules pacemaker (cNSA) présentent une phase spontanée de dépolarisation diastolique (DD), qui mène le potentiel de membrane de la fin de la repolarisation du potentiel d’action (PA) au seuil de déclenchement du PA suivant. Cette activité spontanée implique plusieurs canaux ioniques à la surface de la membrane plasmique et la dynamique calcique intracellulaire. Les cardiomyocytes contractiles du myocarde expriment majoritairement le canal calcique Cav1.2 tandis que les cNSA en expriment d’autres isoformes. Ce sont les canaux calciques de type L (LTCC) Cav1.3 et de type T (TTCC) Cav3.1, qui sont impliqués dans la DD. Les souris génétiquement modifiées pour Cav1.3 et/ou Cav3.1 ont des caractéristiques physiopathologiques et sont utilisées comme modèle d’étude des dysfonctions sinusales de l’homme. La cartographie optique du NSA isolé a permis de révéler une activité électrophysiologique intrinsèque altérée par les mutations. L’expérimentation en patch clamp et en imagerie calcique des cNSA isolées montrent que les mutations altèrent la mécanistique cellulaire du pacemaker. Le couplage de ces approches à l’utilisation d’outils pharmacologiques spécifiques a permis d’évaluer la contribution des différents éléments à cette mécanistique cellulaire et de préciser les controverses sur les fondements de l’automatisme cardiaque. Cette thématique de recherche présente des enjeux majeurs dans le domaine de la santé puisque les perspectives thérapeutiques et les stratégies pharmacologiques pour traiter les dysfonctions sinusales nécessitent une connaissance intégrale du mécanisme. / Heart automaticity is generated by a basic pacemaker mechanism not fully understood and still controversial. Pacemaker activity is initiated by specialized cardiomyocytes in the Sino-atrial node (SAN). The spontaneous phase of diastolic depolarization (DDP) characterizes SAN cells (SANc). This phase drives the membrane potential of SANc from the end of the repolarization to the threshold of the next action potential (AP). This spontaneous activity involves several ion channels on the plasma membrane and the intracellular dynamic of calcium. In terms of calcium channels, atrial and ventricular cardiomyocytes express mostly Cav1.2 whereas SANc express two additional isoforms. Specifically, in SANc are expressed Cav1.3 LTCC (L type Calcium channels) and the Cav3.1 TTCC (T type Calcium channels), which are activated during the DD. Genetically modified mice inactivated for Cav1.3, Cav3.1 and Cav1.3/Cav3.1 we generated and used as a models of study of human SAN dysfunctions. In particular, we highlighted the impairment of the pacemaker activity in these mice by optical mapping of the intact SAN, and by patch clamping and calcium imaging of isolated SANc. Coupling this approaches with pharmacological tools allowed us to evaluating the contribution of the various elements constituting to the pacemaker mechanism. This thematic of research presents major issues in terms of public health. Indeed, we need a better understanding of the pacemaker mechanism to develop pharmacological strategies against SAN dysfunction.