Abstract
Calcium (Ca2+) is a universal regulator of various cellular functions. In cardiomyocytes, Ca2+ is the central element of excitation-contraction coupling, but also impacts diverse signaling cascades and influences the regulation of gene expression, referred to as excitation-transcription coupling. Disturbances in cellular Ca2+-handling and alterations in Ca2+-dependent gene expression patterns are pivotal characteristics of failing cardiomyocytes, with several excitation-transcription coupling pathways shown to be critically involved in structural and functional remodeling processes. Thus, targeting Ca2+-dependent transcriptional pathways might offer broad therapeutic potential. In this article, we (1) review cytosolic and nuclear Ca2+ dynamics in cardiomyocytes with respect to their impact on Ca2+-dependent signaling, (2) give an overview on Ca2+-dependent transcriptional pathways in cardiomyocytes, and (3) discuss implications of excitation-transcription coupling in the diseased heart.
Highlights
Calcium (Ca2+) is a universal regulator of various cellular functions
Especially signaling cascades involving CaMKII (Ca2+/calmodulin-dependent kinase II) and the Ca2+/calmodulin-dependent serine/threonine phosphatase calcineurin have been extensively characterized on their role in cardiac hypertrophy and remodeling processes.[5,6]
In the same setting of ischemia/reperfusion injury, we found that CaMKII induces transcription and secretion of the chemokines CCL2 and CCL3 from cardiomyocytes, thereby triggering an intrinsic chemoattractant cardiomyocyte signaling cascade that is associated with scar formation and cardiac fibrosis.[87]
Summary
ANGII AP-1 AR ATF1 CaMKII CAMTA CnA CnB CREB EC ET ET-1 HDAC HP1 IGF-1 IP3 IRF8 LTCC MCIP1 MEF2 NCX NFAT NFκB NPC PKA PKC PLC PLN RyR SERCA SOCE SR SRF STIM1 TRP TXNIP angiotensin 2 activator protein 1 adrenergic receptor activating transcription factor 1 Ca2+/calmodulin-dependent kinase II calmodulin-binding transcription activator calcineurin subunit A Ca2+-binding regulatory subunit B cAMP response element binding protein excitation–contraction excitation–transcription endothelin-1 histone deacetylase heterochromatin protein 1 insulin-like growth factor 1 inositol 1,4,5-trisphosphate interferon regulatory factor 8 L-type Ca2+ channel myocyte-enriched calcineurin-interacting protein 1 myocyte enhancer factor 2 Na+/Ca2+ exchanger nuclear factor of activated T cells nuclear factor κB nuclear pore complex protein kinase A protein kinase C phospholipase C phospholamban ryanodine receptor SR Ca2+ ATPase store-operated Ca2+ entry sarcoplasmic reticulum serum response factor stromal interaction molecule 1 transient receptor potential thioredoxin-interacting protein. The physiological relevance of this finding is still unclear, yet one has to consider that Ca2+, locally enhanced in nuclear microdomains, might bind to a very specific region of the DNA and recruit Ca2+dependent enzymes to spatially modify chromatin structure and potentially change transcription
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