2026-07-21T14:15:14Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/152612024-09-27T09:05:53Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
Macias, Alvaro
author
González-Guerra, Andrés
author
Moreno-Manuel, Ana I.
author
Cruz, Francisco M.
author
García-Quintáns, Nieves
author
Gutiérrez, Lilian K.
author
Roche-Molina, Marta
author
Bermúdez-Jiménez, Francisco
author
Vera-Pedrosa, María L.
author
Martínez-Carrascoso, Isabel
author
Bernal, Juan A.
author
Jalife, Jose
2022-12-07T16:05:34Z
2022-12-07T16:05:34Z
2021
Heart rhythm: the official journal of the Heart Rhythm Society 18(8):S35
10.1016/j.hrthm.2021.06.103
1547-5271
Heart Rhythm
http://hdl.handle.net/20.500.12105/15261
Background: The strong inward rectifier K+ channel, Kir2.1, is
known to localize at the sarcolemma to control the resting
potential and the final phase of ventricular repolarization. K+
channels have been suggested to contribute countercurrent to
calcium flux across the sarcoplasmic reticulum (SR) membrane,
but their identity and function remain controversial.
Objective: To test whether a fraction of Kir2.1 channels that
cluster within a novel SR membrane microdomain function to
provide essential countercurrent to balance Ca2+ reuptake,
helping to control intracellular calcium dynamics and excitationcontraction coupling.
Methods: Using confocal microscopy we analyzed the
ultrastructure of mouse and rat skeletal muscle slices,
cardiomyocytes, and isolated mouse cardiac SR vesicles.
Immunolocalization of target proteins was analyzed in intact and
detubulated cardiomyocytes treated with formamide by
immunofluorescence and biochemically by western-blotting after
membrane fractionation. Functional assays included patchclamping and calcium transient dynamics.
Results: Cardiomyocytes and skeletal muscle slices revealed two
distinct microdomain bands of Kir2.1 immunostaining, one
colocalizing with NaV1.5 near the Z disk, the other colocalizing with
Ankyrin-B in the M line. The latter is a previously unknown Kir2.1
channel microdomain localized at the SR membrane. Its ionic
current was sensitive to spermine and caffeine, and modified by
asymmetrical potassium concentrations. Finally, chloroquinemediated inhibition of the SR Kir2.1 current resulted in a larger but
slower calcium SR reuptake. Hence, we revealed a previously
unknown physiological role for Kir2.1 channels at the SR
membrane in the control of intracellular Ca2+ dynamics, conducting
K+ as a potential countercurrent ion to calcium reuptake.
Conclusion: Altogether, the data provide original structural and
functional demonstration of a major K+ channel localizing at the
SR and contributing to the control of intracellular calcium homeostasis. Aberrant Kir2.1 localization at the SR could underly
cardiac arrhythmogenesis and periodic skeletal muscle paralysis
in several inheritable ion channel diseases.
eng
B-AB18-02 KIR2.1 CHANNELS IN A NOVEL SARCOPLASMIC RETICULUM MICRODOMAIN CONTROL INTRACELLULAR CA2+ DYNAMICS
conference presentation
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B_AB18_02 HEART RHYTHM KIR2_1 CHANNELS IN A NOVEL SARCOPLASMIC RETICULUM MICRODOMAIN CONTROL INTRACELLULAR CA2DYNAMICS.pdf
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B_AB18_02 HEART RHYTHM KIR2_1 CHANNELS IN A NOVEL SARCOPLASMIC RETICULUM MICRODOMAIN CONTROL INTRACELLULAR CA2DYNAMICS.pdf.txt