Stochastic aspects of transmitter release and bioenergetic dysfunction in isolated nerve terminals

Synaptosomes (isolated nerve terminals) have been studied for more than 40 years. The preparation allows aspects of transmitter metabolism and release to be studied ex vivo from specific brain regions of animals of any age. Conditions can be devised to enable the terminals to fire spontaneous action potentials, allowing the presynaptic control of glutamate exocytosis to be studied. Recent developments have greatly increased the sensitivity with which the bioenergetics of the intra-synaptosomal mitochondria can be investigated.

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The increase of extracellular Ca2+ from physiological concentrations to hypercalcemia impairs sino-atrial automaticity

EP Europace ◽

10.1093/europace/euab116.567 ◽

2021 ◽

Vol 23 (Supplement_3) ◽

Author(s):

AG Torrente ◽

L Fossier ◽

M Baudot ◽

E Torre ◽

I Bidaud ◽

...

Keyword(s):

Action Potentials ◽

Ex Vivo ◽

Pacemaker Activity ◽

Funding Source ◽

Cell Contractility ◽

Funding Sources ◽

Spontaneous Action ◽

Spontaneous Action Potentials ◽

Ca2 Channels ◽

Funding Acknowledgements

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): ESC FRM Lefoulon Delalande Aims To investigate whether extracellular hypercalcemia alters the conduction through L-type Ca2+ channels (LTCCs), impairing the pacemaker activity of the heart. Introduction In the sino-atrial node (SAN), membrane currents and the dynamics of intracellular Ca2+ ([Ca2+]i) generate the pacemaker activity of the heart. SAN dysfunctions (SNDs) harm heart automaticity and have been associated with abnormal dynamics of [Ca2+]i. The LTCCs, Cav1.2 and Cav1.3 carry the main Ca2+ influx of SAN cells, which is necessary to sustain [Ca2+]i dynamics. Modified extracellular Ca2+ ([Ca2+]o) could alter Ca2+ influx through these channels. For example, cancer and hyperparathyroidism can raise [Ca2+]o, causing an extracellular hypercalcemia that could alter [Ca2+]i dynamics and impair SAN activity and heart automaticity. Methods and results To test this hypothesis, we measured contractions, [Ca2+]i release and L-type Ca2+ current (ICa,L) in spontaneous cells of the murine SAN. Then, we recorded rate and propagation of the spontaneous action potentials (APs) generated by the SAN tissue ex-vivo. In spontaneously beating SAN cells, we observed that the modification of [Ca2+]o affected [Ca2+]i and cell contractility through changes of ICa,L. In particular, the increase of [Ca2+]o dysregulated pacemaker activity, likely through excessive Ca2+ influx mediated by Cav1.2. [Ca2+]o increase to hypercalcemia induced arrhythmia also in the intact SAN tissues, activating ectopic leading regions of pacemaking and impairing conduction towards the atria. Conclusions Hypercalcemia causes excessive Cav1.2-mediated Ca2+ influx, which alters [Ca2+]I leading to pacemaker impairment. Modulation of LTCC may reduce pacemaker dysfunctions, preventing SND progression.

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