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A novel Na+ channel splice form contributes to the regulation of an androgen-dependent social signal.

ABSTRACT: Na(+) channels are often spliced but little is known about the functional consequences of splicing. We have been studying the regulation of Na(+) current inactivation in an electric fish model in which systematic variation in the rate of inactivation of the electric organ Na(+) current shapes the electric organ discharge (EOD), a sexually dimorphic, androgen-sensitive communication signal. Here, we examine the relationship between an Na(+) channel (Na(v)1.4b), which has two splice forms, and the waveform of the EOD. One splice form (Na(v)1.4bL) possesses a novel first exon that encodes a 51 aa N-terminal extension. This is the first report of an Na(+) channel with alternative splicing in the N terminal. This N terminal is present in zebrafish suggesting its general importance in regulating Na(+) currents in teleosts. The extended N terminal significantly speeds fast inactivation, shifts steady-state inactivation, and dramatically enhances recovery from inactivation, essentially fulfilling the functions of a beta subunit. Both splice forms are equally expressed in muscle in electric fish and zebrafish but Na(v)1.4bL is the dominant form in the electric organ implying electric organ-specific transcriptional regulation. Transcript abundance of Na(v)1.4bL in the electric organ is positively correlated with EOD frequency and lowered by androgens. Thus, shaping of the EOD waveform involves the androgenic regulation of a rapidly inactivating splice form of an Na(+) channel. Our results emphasize the role of splicing in the regulation of a vertebrate Na(+) channel and its contribution to a known behavior.

SUBMITTER: Liu H

PROVIDER: S-EPMC2615813 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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A novel Na+ channel splice form contributes to the regulation of an androgen-dependent social signal.

Liu He H Wu Ming-ming MM Zakon Harold H HH

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080901 37

Na(+) channels are often spliced but little is known about the functional consequences of splicing. We have been studying the regulation of Na(+) current inactivation in an electric fish model in which systematic variation in the rate of inactivation of the electric organ Na(+) current shapes the electric organ discharge (EOD), a sexually dimorphic, androgen-sensitive communication signal. Here, we examine the relationship between an Na(+) channel (Na(v)1.4b), which has two splice forms, and the ...[more]

PMID: 18784298

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Project description:Human gene variants affecting ion channel biophysical activity and/or membrane localization are linked to potentially fatal cardiac arrhythmias. However, the mechanism for many human arrhythmia variants remains undefined despite more than a decade of investigation. Posttranslational modulation of membrane proteins is essential for normal cardiac function. Importantly, aberrant myocyte signaling has been linked to defects in cardiac ion channel posttranslational modifications and disease. We recently identified a novel pathway for posttranslational regulation of the primary cardiac voltage-gated Na(+) channel (Na(v)1.5) by Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). However, a role for this pathway in cardiac disease has not been evaluated.We evaluated the role of CaMKII-dependent phosphorylation in human genetic and acquired disease. We report an unexpected link between a short motif in the Na(v)1.5 DI-DII loop, recently shown to be critical for CaMKII-dependent phosphorylation, and Na(v)1.5 function in monogenic arrhythmia and common heart disease. Experiments in heterologous cells and primary ventricular cardiomyocytes demonstrate that the human arrhythmia susceptibility variants (A572D and Q573E) alter CaMKII-dependent regulation of Na(v)1.5, resulting in abnormal channel activity and cell excitability. In silico analysis reveals that these variants functionally mimic the phosphorylated channel, resulting in increased susceptibility to arrhythmia-triggering afterdepolarizations. Finally, we report that this same motif is aberrantly regulated in a large-animal model of acquired heart disease and in failing human myocardium.We identify the mechanism for 2 human arrhythmia variants that affect Na(v)1.5 channel activity through direct effects on channel posttranslational modification. We propose that the CaMKII phosphorylation motif in the Na(v)1.5 DI-DII cytoplasmic loop is a critical nodal point for proarrhythmic changes to Na(v)1.5 in congenital and acquired cardiac disease.

Dataset Information

A novel Na+ channel splice form contributes to the regulation of an androgen-dependent social signal.

Publications

A novel Na+ channel splice form contributes to the regulation of an androgen-dependent social signal.

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