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Auxiliary β-Subunits of L-Type Ca2+ Channels in Heart Failure

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Pathologies of Calcium Channels

Abstract

The cardiac L-type Ca2+ channel consists of an ion-conducting channel pore Cav1.2 and auxiliary subunits, namely α2δ- and β-subunits (Cavβ). Four Cavβ isoforms and several splice variants are known to date. Cavβ subunits modulate L-type Ca2+ channels by significantly increasing its activity with Cavβ2 isoforms having the strongest effect. Furthermore, Cavβ subunits are involved in modulation of membrane expression of the channel pore Cav1.2. In human heart failure, density of Ca2+ currents mediated by L-type Ca2+ channels is unchanged and the activity of single L-type Ca2+ channels is significantly increased suggesting a reduced channel expression. The “heart failure phenotype” of single-channel gating might be explained by an altered expression pattern of Cavβ subunits. Indeed cardiac Cavβ2 isoforms are upregulated in human heart failure. Targeted overexpression of Cavβ2 subunits in murine hearts mimicked L-type Ca2+ channel features typical for human heart failure and furthermore induced cardiac hypertrophy and contractile dysfunction. Lowering cardiac Cavβ2 expression attenuated pressure-induced ventricular hypertrophy in rats and appeared to be well tolerated in mice. These findings strongly support the idea that Cavβ2 subunits are of pathophysiological relevance for development of cardiac hypertrophy and heart failure and a promising target for future treatment options.

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Acknowledgments

We thank Lori Borgal for language editing of the manuscript. The permissions of AHA Journals to show Fig. 14.2 taken from Schröder et al. (Circulation 98(10):969–976) and by Oxford Journals to show Fig. 14.3 taken from Beetz et al. (Cardiovasc Res 84(3):396–406; doi: 10.1093/cvr/cvp251) are appreciated.

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  1. Department of Pharmacology, University of Cologne, Cologne, Germany

    Jan Matthes & Stefan Herzig

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  1. Jan Matthes
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  2. Stefan Herzig
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Correspondence to Stefan Herzig .

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  1. Hotchkiss Brain Institute, Department of Physiology and Pharmacology, University of Calgary, Calgary, Canada

    Norbert Weiss

  2. Department of Neurophysiology and Pharmacology, Medical University Vienna, Vienna, Austria

    Alexandra Koschak

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Matthes, J., Herzig, S. (2014). Auxiliary β-Subunits of L-Type Ca2+ Channels in Heart Failure . In: Weiss, N., Koschak, A. (eds) Pathologies of Calcium Channels. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-40282-1_14

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