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* Max Delbrück Center for Molecular Medicine (MDC), D-13092 Berlin, Germany;
Institute of Cardiology, La Habana, Cuba;
Center for Cardiovascular Research, University Medicine Charité, Berlin, Germany;
Medizinische Klinik II, University UK-SH, Campus Lübeck, Germany;
|| Deutsches Herzzentrum, Berlin, Germany;
¶ Physiopathologie Cardiovasculaire, INSERM U-637, Montpellier Cedex 5, France; and
Johannes Müller Institute for Physiology, University Medicine Charité, Berlin, Germany
1Correspondence: Robert-Rössle-Str. 10, Berlin D-13092, Germany. E-mail: haase{at}mdc-berlin.de
Defective L-type Ca2+ channel (ICaL) regulation is one major cause for contractile dysfunction in the heart. The ICaL is enhanced by sympathetic nervous stimulation: via the activation of β-adrenergic receptors, PKA phosphorylates the 
1C(CaV1.2)- and β2-channel subunits and ahnak, an associated 5643-amino acid (aa) protein. In this study, we examined the role of a naturally occurring, genetic variant Ile5236Thr-ahnak on ICaL. Binding experiments with ahnak fragments (wild-type, Ile5236Thr mutated) and patch clamp recordings revealed that Ile5236Thr-ahnak critically affected both β2 subunit interaction and ICaL regulation. Binding affinity between ahnak-C1 (aa 4646-5288) and β2 subunit decreased by 
50% after PKA phosphorylation or in the presence of Ile5236Thr-ahnak peptide. On native cardiomyocytes, intracellular application of this mutated ahnak peptide mimicked the PKA-effects on ICaL increasing the amplitude by 60% and slowing its inactivation together with a leftward shift of its voltage dependency. Both mutated Ile5236Thr-peptide and Ile5236Thr-fragment (aa 5215-5288) prevented specifically the further up-regulation of ICaL by isoprenaline. Hence, we suggest the ahnak-C1 domain serves as physiological brake on ICaL. Relief from this inhibition is proposed as common pathway used by sympathetic signaling and Ile5236Thr-ahnak fragments to increase ICaL. This genetic ahnak variant might cause individual differences in ICaL regulation upon physiological challenges or therapeutic interventions.—Haase, H., Alvarez, J., Petzhold, D., Doller, A., Behlke, J., Erdmann, J., Hetzer, R., Regitz-Zagrosek, V., Vassort, G., Morano, I. Ahnak is critical for cardiac Ca(v)1.2 calcium channel function and its β-adrenergic regulation.
Key Words: recombinant protein • missense variant • β2 subunit • binding affinity
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