Cardiac Remodeling and Disease: SOCE and TRPC Signaling in Cardiac Pathology

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.

Keywords: Calcineurin; Cardiac hypertrophy; Heart failure; NFAT; TRPC.