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

Item Type:Article
Title:Ahnak1 is a tuneable modulator of cardiac Ca(v)1.2 calcium channel activity
Creators Name:Pankonien, I. and Alvarez, J.L. and Doller, A. and Koehncke, C. and Rotte, D. and Regitz-Zagrosek, V. and Morano, I. and Haase, H.
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 Cav{beta}(2) subunit. In this study, we addressed the question whether ahnak1/Cav{beta}(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 Cav{beta}(2) interaction as assessed by recombinant proteins. But, we observed a robust increase in Cav{beta}(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 Cav{beta}(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/Cav{beta}(2) interaction provides a tool for modulating the beta-adrenergic response of I (CaL).
Keywords:Fight-or-Flight Response, Cav1.2 Channel Current, Cav{beta}2, SNP, Ahnak1, Animals, Mice
Source:Journal of Muscle Research and Cell Motility
Page Range:281-290
Date:December 2011
Official Publication:https://doi.org/10.1007/s10974-011-9269-2
PubMed:View item in PubMed

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