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PNAS 107 (12): 5658-5663

Copyright © 2010 by the National Academy of Sciences.


Non–Ca2+-conducting Ca2+ channels in fish skeletal muscle excitation-contraction coupling

Johann Schredelseker, Manisha Shrivastav, Anamika Dayal, and Manfred Grabner1

Department of Medical Genetics, Molecular and Clinical Pharmacology, Division of Biochemical Pharmacology, Innsbruck Medical University, A-6020 Innsbruck, Austria

Edited* by Clara Franzini-Armstrong, University of Pennsylvania Medical Center, Philadelphia, PA, and approved February 1, 2010 (received for review October 21, 2009)

Abstract: During skeletal muscle excitation-contraction (EC) coupling, membrane depolarizations activate the sarcolemmal voltage-gated L-type Ca2+ channel (CaV1.1). CaV1.1 in turn triggers opening of the sarcoplasmic Ca2+ release channel (RyR1) via interchannel protein–protein interaction to release Ca2+ for myofibril contraction. Simultaneously to this EC coupling process, a small and slowly activating Ca2+ inward current through CaV1.1 is found in mammalian skeletal myotubes. The role of this Ca2+ influx, which is not immediately required for EC coupling, is still enigmatic. Interestingly, whole-cell patch clamp experiments on freshly dissociated skeletal muscle myotubes from zebrafish larvae revealed the lack of such Ca2+ currents. We identified two distinct isoforms of the pore-forming CaV1.1{alpha}1S subunit in zebrafish that are differentially expressed in superficial slow and deep fast musculature. Both do not conduct Ca2+ but merely act as voltage sensors to trigger opening of two likewise tissue-specific isoforms of RyR1. We further show that non-Ca2+ conductivity of both CaV1.1{alpha}1S isoforms is a common trait of all higher teleosts. This non-Ca2+ conductivity of CaV1.1 positions teleosts at the most-derived position of an evolutionary trajectory. Though EC coupling in early chordate muscles is activated by the influx of extracellular Ca2+, it evolved toward CaV1.1-RyR1 protein–protein interaction with a relatively small and slow influx of external Ca2+ in tetrapods. Finally, the CaV1.1 Ca2+ influx was completely eliminated in higher teleost fishes.

Key Words: calcium conductivity • evolution • ion channels • slow and fast muscle • zebrafish

Author contributions: J.S., A.D., and M.G. designed research; J.S., M.S., A.D., and M.G. performed research; J.S., M.S., and M.G. analyzed data; and J.S. and M.G. wrote the paper.

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

Data deposition: Sequences for zf-{alpha}1S-a and zf-{alpha}1S-b have been deposited in the GenBank database (accession nos. FJ769223 and AY495698).

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: manfred.grabner{at}

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