In cardiac myocytes, discrete clusters of ion channels and regulatory receptors are present in the sarcolemma, where they form an interacting network and work together as a part of macro-molecular functional signaling complex. A number of important protein-interacting networks have been recently identified in association with various subcellular microdomains, including transversal-axial tubular system, lipid rafts/caveolae, costameres, and intercalated discs. Compartmentalized distribution of proteins may impact their function and regulation by various neurohormonal pathways, either via a direct interaction or by second messengers through different G-protein-coupled receptors. This enables the specificity, reliability and accuracy of the autonomic modulation of excitation–contraction processes in cardiac myocytes.

Recent methodological advances have made it possible to routinely image the topography of live cardiomyocytes, allowing the study of clustering functional ion channels and receptors as well as their coupling within a specific microdomain. Novel biosensors for live cell imaging as well as sophisticated biochemical, electrophysiological and non-optical imaging techniques, have been developed and widely applied to cardiac myocytes to ascertain for second messenger compartmentation. These resulted in a better understanding of functionality of subcellular microdomains in healthy cardiomyocytes and in pathological settings. The emerging evidence demonstrate that alterations of spatial compartmentation of ion channels and receptors could be crucial for pathological remodeling, in addition to classically appreciated changes in protein expression and posttranslational modifications. This extends beyond the classical concept of electric remodeling and adds a new dimension to cardiovascular disease.

The purpose of this Research Topic is to summarize recent advances on microdomain-specific distribution, functioning, regulation, and remodeling of ion channels, regulatory proteins and second messengers, and their contributions to the cellular signaling and cardiac pathology. We welcome experts on this research topic to share their original research as well as methods and opinions on this topic, to submit solid review papers and perspectives to bring forward hypotheses that provide new avenues in this emerging concept with promising clinical implications.

Keywords: Cardiomyocyte structure, Microdomain, Macromolecular complex, Signaling compartmentalization, Cardiac remodeling

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