Striatin knock out induces a gain of function of I Na and impaired Ca 2+ handling in mESC-derived cardiomyocytes.

Autor: Benzoni P; Department of Biosciences, The Cell Physiology MiLab, Università Degli Studi Di Milano, Milan, Italy., Arici M; Department of Biotecnologie e Bioscienze, Università degli Studi di Milano Bicocca Milano, Milan, Italy., Giannetti F; Department of Biosciences, The Cell Physiology MiLab, Università Degli Studi Di Milano, Milan, Italy., Cospito A; Department of Biosciences, The Cell Physiology MiLab, Università Degli Studi Di Milano, Milan, Italy., Prevostini R; Department of Biosciences, The Cell Physiology MiLab, Università Degli Studi Di Milano, Milan, Italy., Volani C; Department of Biosciences, The Cell Physiology MiLab, Università Degli Studi Di Milano, Milan, Italy.; Institute for Biomedicine, Eurac Research, Bolzano, Italy., Fassina L; Department of Electrical, Computer and Biomedical Engineering, University of Pavia, Pavia, Italy., Rosato-Siri MD; Institute for Biomedicine, Eurac Research, Bolzano, Italy., Metallo A; Department of Biotecnologie e Bioscienze, Università degli Studi di Milano Bicocca Milano, Milan, Italy., Gennaccaro L; Institute for Biomedicine, Eurac Research, Bolzano, Italy., Suffredini S; Institute for Biomedicine, Eurac Research, Bolzano, Italy., Foco L; Institute for Biomedicine, Eurac Research, Bolzano, Italy., Mazzetti S; Department of Biosciences, Università Degli Studi Di Milano, Milan, Italy., Calogero A; Department of Biosciences, Università Degli Studi Di Milano, Milan, Italy., Cappelletti G; Department of Biosciences, Università Degli Studi Di Milano, Milan, Italy., Leibbrandt A; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Elling U; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Broso F; Institute for Biomedicine, Eurac Research, Bolzano, Italy., Penninger JM; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.; Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada., Pramstaller PP; Institute for Biomedicine, Eurac Research, Bolzano, Italy., Piubelli C; Institute for Biomedicine, Eurac Research, Bolzano, Italy., Bucchi A; Department of Biosciences, The Cell Physiology MiLab, Università Degli Studi Di Milano, Milan, Italy., Baruscotti M; Department of Biosciences, The Cell Physiology MiLab, Università Degli Studi Di Milano, Milan, Italy., Rossini A; Institute for Biomedicine, Eurac Research, Bolzano, Italy., Rocchetti M; Department of Biotecnologie e Bioscienze, Università degli Studi di Milano Bicocca Milano, Milan, Italy., Barbuti A; Department of Biosciences, The Cell Physiology MiLab, Università Degli Studi Di Milano, Milan, Italy.
Jazyk: angličtina
Zdroj: Acta physiologica (Oxford, England) [Acta Physiol (Oxf)] 2024 Aug; Vol. 240 (8), pp. e14160. Date of Electronic Publication: 2024 May 15.
DOI: 10.1111/apha.14160
Abstrakt: Aim: Striatin (Strn) is a scaffold protein expressed in cardiomyocytes (CMs) and alteration of its expression are described in various cardiac diseases. However, the alteration underlying its pathogenicity have been poorly investigated.
Methods: We studied the role(s) of cardiac Strn gene (STRN) by comparing the functional properties of CMs, generated from Strn-KO and isogenic WT mouse embryonic stem cell lines.
Results: The spontaneous beating rate of Strn-KO CMs was faster than WT cells, and this correlated with a larger fast I Na conductance and no changes in I f . Paced (2-8 Hz) Strn-KO CMs showed prolonged action potential (AP) duration in comparison with WT CMs and this was not associated with changes in I CaL and I Kr . Motion video tracking analysis highlighted an altered contraction in Strn-KO CMs; this was associated with a global increase in intracellular Ca 2+ , caused by an enhanced late Na + current density (I NaL ) and a reduced Na + /Ca 2+ exchanger (NCX) activity and expression. Immunofluorescence analysis confirmed the higher Na + channel expression and a more dynamic microtubule network in Strn-KO CMs than in WT. Indeed, incubation of Strn-KO CMs with the microtubule stabilizer taxol, induced a rescue (downregulation) of I Na conductance toward WT levels.
Conclusion: Loss of STRN alters CMs electrical and contractile profiles and affects cell functionality by a disarrangement of Strn-related multi-protein complexes. This leads to impaired microtubules dynamics and Na + channels trafficking to the plasma membrane, causing a global Na + and Ca 2+ enhancement.
(© 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)
Databáze: MEDLINE
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