Electrophysiological models of the human pancreatic δ-cell: From single channels to the firing of action potentials.

Minimal mathematical models were developed to describe the electrophysiological properties of human δ-cells. Markov models of single channels were first developed based on the analysis of electrophysiological data. Monte Carlo simulations of voltage-clamp experiments were performed in an iteratively optimization procedure to estimate the number of channels required to reproduce the main characteristics of the macroscopic currents recorded experimentally. A membrane model of the firing of action potentials was then developed based on the kinetic schemes of single channels and the number of channels estimated. We showed that macroscopic currents of human δ-cells can be reproduced by minimal models of single channels when the appropriate number of channels is considered. In addition, our simulations suggest that human δ-cells are capable of generating action potentials through the interaction of the ionic currents involved. Finally, we determined the relative contribution of the currents underlying the firing of action potentials in human pancreatic δ-cells, which allowed us to propose a qualitative model of an action potential in terms of the underlying ionic currents.

Minimal state models for ionic channels involved in glucagon secretion.

Pancreatic alpha cells synthesize and release glucagon. This hormone along with insulin, preserves blood glucose levels within a physiological range. During low glucose levels, alpha cells exhibit electrical activity related to glucagon secretion. In this paper, we introduce minimal state models for those ionic channels involved in this electrical activity in mice alpha cells. For estimation of model parameters, we use Monte Carlo algorithms to fit steady-state channel currents. Then, we simulate dynamic ionic currents following experimental protocols. Our aims are 1) To understand the individual ionic channel functioning and modulation that could affect glucagon secretion, and 2) To simulate ionic currents actually measured in voltage-clamp alpha-cell experiments in mice. Our estimations indicate that alpha cells are highly permeable to sodium and potassium which mainly manage action potentials. We have also found that our estimated N-type calcium channel population and density in alpha cells is in good agreement to those reported for L-type calcium channels in beta cells. This finding is strongly relevant since both, L-type and N-type calcium channels, play a main role in insulin and glucagon secretion, respectively.

Exocytotic dynamics and calcium cooperativity effects in the calyx of Held synapse: a modelling study.

A stochastic computational approach to the study of secretory processes at the calyx of Held synapse is presented in this paper. The calyx of Held is a giant synapse located in the brainstem which is widely used for experimental recording of neurotransmitter release. We focus on the study of the exocytotic dynamics for a pool of readily releasable vesicles using a Monte Carlo simulation scheme that includes models for the P-type calcium channels, the kinetic reactions of endogenous and exogenous (mobile) buffers, the kinetic reactions for the secretory vesicles, as well as the microscopic diffusion of mobile buffers and calcium ions. The simulations are performed in a 3-D orthogonal grid which approximates a cylindrical domain representing an active zone of the presynaptic terminal of the calyx. For this domain, we quantify the release rates related to calcium currents in response to depolarizing voltage pulses. The influence on simulated pulse/action potential depolarization protocols of the kinetic scheme for the calcium sensor of vesicles and the geometry of calcium channels for the kinetic cooperativity for release, is analyzed at a microdomain level. Among other aspects, our results suggest that the spatial organization of Ca2+ channels could have measurable effects in the kinetic cooperativity which could reflect developing changes in the calyx of Held synapse.

Software for simulating calcium-triggered exocytotic processes.

We describe a software package for the simulation of exocytotic events from readily releasable pools of secretory vesicles in neuroendocrine cells and presynaptic terminals. The visual package Ca3D_Exolab simulates the entry of Ca(2+) through the calcium channels, the kinetic reactions of calcium with buffers, the diffusion of calcium and mobile buffers, and the kinetic reactions of calcium with the secretory vesicles. The location of both channels and secretory vesicles can be set by using a graphical interface. Calcium and buffer concentrations at different depths from the cellular membrane and capacitance time courses are obtained as outputs. The software package also provides a descriptive statistical data analysis of the different output data.

Relación entre el nivel socioeconómico y hábitos de vida con el fibrinógeno y el factor von Willebrand en venezolanos sanos y con cardiopatía isquémica / Relation between socioeconomic levels and life style with fibrinogen and von Willebrand factor in Venezuela

Estudios epidemiológicos en Europa, EEUU y Japón, han revelado una relación inversa entre la concentración de fibrinógeno y del factor von Willebrand con el nivel socioeconómico. En este trabajo se presentan los resultados de la relación entre el fibrinógeno y el factor von Willebrand con el nivel socioeconómico, los hábitos tabáquicos, alcohólicos, actividad física y la edad, en una población venezolana aparentemente sana de 978 hombres y 968 mujeres (grupo control), y en 172 hombres y 78 mujeres con Enfermedad Cardiovascular Isquémica. Se consideró factor de riesgo comportamiento para niveles altos de fibrinógeno y factor von Willebrand, la presencia de uno o más de los siguientes hábitos: ser fumador o ex-fumador de menos de 5 años, no ingerir alcohol o ingerirlo en exceso, y el tener una actividad física muy limitada. En los controles, la edad tuvo un efecto significativo y positivo sobre las dos variables hemostáticas, en ambos sexos. En relación al efecto del nivel socioeconómico, se observó una tendencia en ambas variables de mostrar las concentraciones más altas en los niveles más bajos, sólo significativa en las mujeres. En cambio, el factor de riesgo comportamiento no tuvo un efecto significativo sobre ninguna de las dos variables. En los pacientes, la edad no tuvo efecto sobre ninguna de las variables, el factor de riesgo comportamiento tuvo un efecto significativo positivo sólo sobre el fibrinógeno de los hombres, y el nivel socioeconómico sólo tuvo efectos significativos en la concentración de fibrinógeno de las mujeres: valores altos en niveles socioeconómicos bajos. Se recomienda continuar con estos estudios para entender mejor la relación entre el nivel socioeconómico, las variables hemostáticas y la incidencia de Enfermedad Cardiovascular Isquémica