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Adrenergic control of cardiac gap junction function and expression

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Abstract

Electrical intercellular communication in the heart allows the propagation of an action potential from cell to cell. This is realized by low-ohmic cell-to-cell channels, the gap junction channels, which are dodecameric proteins consisting of two hexameric hemichannels. Each of the neighbouring cell provides one hemichannel, which consists of six connexins. In the heart, the connexin isoforms Cx43, Cx40 and Cx45 are present with Cx43 being the most abundant isoform. This intercellular communication is regulated acutely by control of the gap junction conductance and chronically by control of the connexin expression. The short half-life time of Cx43 indicates the permanent adaptation of cell communication to the actual requirements. β-Adrenoceptor stimulation enhances Cx40- but reduces Cx45-conductance, while Cx43 channels in most species do not seem to be acutely affected by β-adrenoceptor signalling. In contrast, chronic exposure to β-adrenergic stimulants activates protein kinase A and the mitogenic-activated protein kinase cascade (including protein 38 (p38), mitogenic-activated protein kinase kinase 1, extracellular signal-regulated kinase (ERK)1/2 and c-JUN NH2 terminal kinase (JNK)), the calcineurin pathway, translocation of activator protein 1 (AP1), CRE-binding protein and nuclear factor of activated T cells, finally leading to enhanced Cx43-mRNA and Cx43-protein expression together with Cx43 phosphorylation, but does not affect Cx40. α-Adrenoceptors also play a role in controlling cardiac intercellular communication: α-adrenergic stimulation acutely uncouples the cells, while a chronic stimulation enhances Cx43 expression via protein kinase C, p38, ERK1/2, JNK, c-fos and AP1, but does not alter Cx40 expression. While general cardiac protein synthesis, e.g. of β-actin, is controlled via α1A-adrenoceptors, Cx43 expression is regulated via α1D-adrenoceptors. However, α-adrenoceptor density in the heart varies among species, with high abundance in rat heart and low in human heart. Acute α-adrenergic stimulation, e.g. during ischemia, can lead to uncoupling and facilitates re-entrant arrhythmia. Chronic adrenergic upregulation of Cx43 expression seems to be involved in cardiac hypertrophy. In maladaptive hypertrophy, the enhanced Cx43 is increasingly incorporated in the lateral membrane of the cells rather at the cell poles, which may mean a gap junction disarray. This could—together with a mismatch in cell size and coupling—contribute to arrhythmogenesis. Thus, cardiac adrenoceptors are directly involved in the control of intercellular electrical communication and thus probably are a critical factor in the maintenance of regular cell-to-cell conduction and of the cardiac electrical networking. They probably are involved in the formation of an arrhythmogenic substrate in certain heart diseases.

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  1. Clinic for Paediatric Cardiology, Heart Centre, University of Leipzig, Strümpellstraße. 39, 04289, Leipzig, Germany

    Aida Salameh

  2. Clinic for Cardiac Surgery, University of Leipzig, Leipzig, Germany

    Stefan Dhein

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  1. Aida Salameh
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  2. Stefan Dhein
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Correspondence to Aida Salameh.

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Salameh, A., Dhein, S. Adrenergic control of cardiac gap junction function and expression. Naunyn-Schmied Arch Pharmacol 383, 331–346 (2011). https://doi.org/10.1007/s00210-011-0603-4

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