Optogenetic confirmation of transverse-tubular membrane excitability in intact cardiac myocytes

SCARDIGLI, Marina, Michal PÁSEK, Lorenzo SANTINI, Chiara PALANDRI, Emilia CONTI, Claudia CROCINI, Marina CAMPIONE, Leslie M LOEW, Antoine A F DE VRIES, Daniel A PIJNAPPELS, Francesco S PAVONE, Corrado POGGESI, Elisabetta CERBAI, Raffaele COPPINI, Peter KOHL, Cecilia FERRANTINI and Leonardo SACCONI. Optogenetic confirmation of transverse-tubular membrane excitability in intact cardiac myocytes. Journal of Physiology (London). HOBOKEN: WILEY111, 2024, vol. 602, No 5, p. 791-808. ISSN 0022-3751. Available from: https://dx.doi.org/10.1113/JP285202.

Basic information

• Original name: Optogenetic confirmation of transverse-tubular membrane excitability in intact cardiac myocytes
• Authors: SCARDIGLI, Marina, Michal PÁSEK (203 Czech Republic, belonging to the institution), Lorenzo SANTINI, Chiara PALANDRI, Emilia CONTI, Claudia CROCINI, Marina CAMPIONE, Leslie M LOEW, Antoine A F DE VRIES, Daniel A PIJNAPPELS, Francesco S PAVONE, Corrado POGGESI, Elisabetta CERBAI, Raffaele COPPINI, Peter KOHL, Cecilia FERRANTINI and Leonardo SACCONI.
• Edition: Journal of Physiology (London), HOBOKEN, WILEY111, 2024, 0022-3751.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 30105 Physiology
• Country of publisher: United States of America
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 5.500 in 2022
• Organization unit: Faculty of Medicine
• Doi: http://dx.doi.org/10.1113/JP285202
• UT WoS: 001160656600001
• Keywords in English: cardiac electrophysiology; excitation-contraction coupling; imaging
• Tags: 14110515, rivok
• Tags: International impact, Reviewed

Abstract

T-tubules (TT) form a complex network of sarcolemmal membrane invaginations, essential for well-co-ordinated excitation-contraction coupling (ECC) and thus homogeneous mechanical activation of cardiomyocytes. ECC is initiated by rapid depolarization of the sarcolemmal membrane. Whether TT membrane depolarization is active (local generation of action potentials; AP) or passive (following depolarization of the outer cell surface sarcolemma; SS) has not been experimentally validated in cardiomyocytes. Based on the assessment of ion flux pathways needed for AP generation, we hypothesize that TT are excitable. We therefore explored TT excitability experimentally, using an all-optical approach to stimulate and record trans-membrane potential changes in TT that were structurally disconnected, and hence electrically insulated, from the SS membrane by transient osmotic shock. Our results establish that cardiomyocyte TT can generate AP. These AP show electrical features that differ substantially from those observed in SS, consistent with differences in the density of ion channels and transporters in the two different membrane domains. We propose that TT-generated AP represent a safety mechanism for TT AP propagation and ECC, which may be particularly relevant in pathophysiological settings where morpho-functional changes reduce the electrical connectivity between SS and TT membranes. imageKey points Cardiomyocytes are characterized by a complex network of membrane invaginations (the T-tubular system) that propagate action potentials to the core of the cell, causing uniform excitation-contraction coupling across the cell. In the present study, we investigated whether the T-tubular system is able to generate action potentials autonomously, rather than following depolarization of the outer cell surface sarcolemma. For this purpose, we developed a fully optical platform to probe and manipulate the electrical dynamics of subcellular membrane domains. Our findings demonstrate that T-tubules are intrinsically excitable, revealing distinct characteristics of self-generated T-tubular action potentials. This active electrical capability would protect cells from voltage drops potentially occurring within the T-tubular network.