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Analysis of Tubular Membrane Networks in Cardiac Myocytes from Atria and Ventricles

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Published on: October 15, 2014

Decrease in the density of t-tubular L-type Ca2+ channel currents in failing ventricular myocytes.

Miwa Horiuchi-Hirose¹, Toshihide Kashihara, Tsutomu Nakada

¹Department of Anatomy and Molecular Pharmacology, Shinshu University School of Medicine, Nagano, Japan.

American Journal of Physiology. Heart and Circulatory Physiology

|January 4, 2011

Summary

Excessive beta-adrenergic stimulation in heart failure reduces the density of L-type calcium channels (LTCCs) in t-tubules, impairing calcium release and potentially causing cardiac dysfunction.

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Area of Science:

Cardiology
Molecular Biology
Physiology

Background:

Cardiac hypertrophy and failure can involve decreased calcium-induced calcium release (CICR) gain, despite normal sarcoplasmic reticulum calcium content and L-type calcium channel (LTCC) current density.
This decrease in CICR gain has been linked to structural changes in dyads or t-tubules (TT).
However, altered LTCC activity at the cell surface suggests a potential issue with TT LTCCs in heart failure.

Purpose of the Study:

To investigate the role of TT LTCC current density in the reduced CICR gain observed in heart failure.
To analyze the impact of excessive beta-adrenergic stimulation on TT LTCCs in a mouse model of heart failure.

Main Methods:

Analysis of LTCC currents in failing ventricular myocytes from mice chronically treated with isoproterenol (Iso).
Detubulation of isolated ventricular myocytes using osmotic shock to assess TT LTCC current density.
Pharmacological analysis of TT LTCC regulation by protein kinases and phosphatases.

Main Results:

Iso-treated mice had intact t-tubules and normal LTCC subunit expression.
Detubulation revealed a halved TT LTCC current density in Iso-treated myocytes compared to controls.
TT LTCCs were insufficiently activated by kinases (other than PKA or CaMKII) and excessively suppressed by protein phosphatase 1/2A in Iso-treated myocytes.

Conclusions:

Excessive beta-adrenergic stimulation leads to decreased TT LTCC current density in heart failure.
This reduction is mediated by altered regulation of TT LTCCs by protein kinases and phosphatases.
The decrease in TT LTCC current density may underlie the reduced CICR gain seen in heart failure.