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J Muscle Res Cell Motil. 2011 Dec;32(4-5):281-90. doi: 10.1007/s10974-011-9269-2. Epub 2011 Oct 29.

Ahnak1 is a tuneable modulator of cardiac Ca(v)1.2 calcium channel activity.

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  • 1Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str.10, 13125, Berlin, Germany.

Abstract

Ahnak1 has been implicated in the beta-adrenergic regulation of the cardiac L-type Ca(2+) channel current (I (CaL)) by its binding to the regulatory Cavβ(2) subunit. In this study, we addressed the question whether ahnak1/Cavβ(2) interactions are essential or redundant for beta-adrenergic stimulation of I (CaL). Three naturally occurring ahnak1 variants (V5075 M, G5242R, and T5796 M) identified by genetic screening of cardiomyopathy patients did essentially not influence the in vitro Cavβ(2) interaction as assessed by recombinant proteins. But, we observed a robust increase in Cavβ(2) binding by mutating Ala at position 4984 to Pro which creates a PxxP consensus motif in the ahnak1 protein fragment. Surface plasmon resonance measurements revealed that this mutation introduced an additional Cavβ(2) binding site. The functionality of A4984P was supported by the specific action of the Pro-containing ahnak1-derived peptide (P4984) in beta-adrenergic regulation of I (CaL). Patch clamp recordings on cardiomyocytes showed that intracellular perfusion of P4984 markedly reduced I (CaL) response to the beta-adrenergic agonist, isoprenaline, while the Ala-containing counterpart failed to affect I (CaL). Interestingly, I (CaL) of ahnak1-deficient cardiomyocytes was not affected by peptide application. Moreover, I (CaL) of ahnak1-deficient cardiomyocytes showed intact beta-adrenergic responsiveness. Similarly isolated ahnak1-deficient mouse hearts responded normally to adrenergic challenge. Our results indicate that ahnak1 is not essential for beta-adrenergic up-regulation of I (CaL) and cardiac contractility in mice. But, tuning ahnak1/Cavβ(2) interaction provides a tool for modulating the beta-adrenergic response of I (CaL).

PMID:
22038483
[PubMed - indexed for MEDLINE]
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