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Cardiac Remodeling and Disease: SOCE and TRPC Signaling in Cardiac Pathology
1Department of Internal Medicine I, Comprehensive Heart Failure Center Würzburg, University Hospital Würzburg, Würzburg, Germany. eder_p@ukw.de.
Abstract:
TRPC channels have been suggested as potential candidates mediating store-operated Ca2+ entry (SOCE) in cardiomyocytes. There is increasing evidence that the TRPC isoforms TRPC1 and TRPC4 might fulfill the function as SOCs, in concert with or in parallel to the key players of SOCE, Orai1, and STIM1. Several other isoforms, e.g., TRPC3, TRPC6, and TRPC7, might rather associate to receptor-activated diacylglycerol (DAG)-sensitive ion channels. However, the exact activation mode has not been elucidated yet, given the characteristic of TRPC channels to heteromerize to unpredictable ion channel assemblies. Despite the incomplete information about TRPC activation, there is common agreement that they are crucial Ca2+ components in cardiac signaling and disease. All TRPC isoforms, TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, and TRPC7, are differentially regulated in cardiac disease, and nearly all of them have been shown to impact cardiac signaling pathways that accelerate cardiac disease development. In particular, the calcineurin-nuclear factor of activated T-cell (NFAT) signaling pathway has repeatedly been linked to a TRPC-dependent Ca2+ influx in cardiomyocytes. Moreover, the protein kinases PKG and PKC have been found to modulate TRPC function and the hypertrophic response. Other signaling molecules, such as the serine/threonine kinase Ca2+/calmodulin-dependent protein kinase II (CamKII) or the oxidative stress molecule, NADPH oxidase 2 (NOX2), have also been related to TRPC-dependent effects in the heart.The present chapter provides a comprehensive overview of TRPC channels as Ca2+ entities in cardiomyocytes, their interplay with Ca2+ signaling pathways, and role in cardiac pathology.
Insights
Transient Receptor Potential Canonical (TRPC) channels are crucial for calcium (Ca2+) signaling in cardiomyocytes. Dysregulation of TRPC channels contributes to cardiac disease development and progression.
Area of Science:
- Cardiology
- Molecular Biology
- Ion Channel Physiology
Background:
- Transient Receptor Potential Canonical (TRPC) channels are implicated in store-operated calcium entry (SOCE) in cardiomyocytes.
- TRPC1 and TRPC4 may function as SOCs alongside Orai1 and STIM1, while other isoforms like TRPC3, TRPC6, and TRPC7 are associated with diacylglycerol-sensitive channels.
- TRPC channels form heteromeric complexes with diverse functional properties, and their precise activation mechanisms remain under investigation.
Purpose of the Study:
- To provide a comprehensive overview of TRPC channels in cardiomyocytes.
- To elucidate the role of TRPC channels in cardiac calcium signaling pathways.
- To examine the involvement of TRPC channels in the development and progression of cardiac diseases.
Main Methods:
- Literature review and synthesis of existing research on TRPC channels in cardiac physiology and pathology.
- Analysis of studies investigating TRPC isoform expression and function in cardiomyocytes.
- Examination of signaling pathways modulated by TRPC channels, including calcineurin-NFAT, PKG, PKC, CamKII, and NOX2.
Main Results:
- TRPC channels are critical Ca2+ regulators in cardiomyocytes, influencing cardiac signaling.
- All TRPC isoforms (TRPC1-TRPC7) are differentially regulated in cardiac disease.
- TRPC channels impact signaling pathways like calcineurin-NFAT, protein kinases, and oxidative stress, accelerating cardiac disease.
Conclusions:
- TRPC channels play a significant role in cardiac calcium homeostasis and signaling.
- Dysregulation of TRPC channels is implicated in the pathogenesis of various cardiac conditions.
- Understanding TRPC channel function is vital for developing therapeutic strategies for heart disease.
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