Ca2+ microdomain-based excitation-transcription coupling in cardiac myocytes and vascular smooth muscle cells

Abstract

Ca²⁺ signals play a crucial role in maintaining cardiovascular homeostasis, including regulation of the heartbeat, blood pressure, and adaptation to changes in the external environment. Conversely, abnormal Ca²⁺ signaling is often involved in the onset and progression of cardiovascular diseases, such as cardiac hypertrophy, heart failure, arteriosclerosis, and hypertension. In excitable cells, such as cardiac myocytes and vascular smooth muscle cells (VSMCs), membrane depolarization, and the subsequent elevation of cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) via voltage-dependent Ca²⁺ channels (VDCCs) cause muscle contraction, which is known as excitation-contraction coupling (E-C coupling). Elevated [Ca²⁺]_cyt can also activate Ca²⁺-dependent enzymes, in some cases leading to changes in gene expression patterns and contributing to long-term cellular responses. This mechanism is referred to as excitation-transcription coupling (E-T coupling), and it is involved in both the adaptive and pathological responses of the cardiovascular system to chronic stimulation. Specific intracellular regions, known as Ca²⁺ microdomains, exhibit localized increases in [Ca²⁺]_cyt. Such localized Ca²⁺ signaling is now known to be one of the molecular mechanisms controlling the diversity of Ca²⁺ responses. These Ca²⁺ microdomains are often formed by complexes consisting of Ca²⁺ channels and downstream Ca²⁺-dependent enzymes localized by scaffolding proteins. This review outlines some of the molecular mechanisms and roles of Ca²⁺ microdomain-based E-T coupling in cardiac myocytes and VSMCs. First, we discuss the major molecular components that are essential for functional Ca²⁺ microdomains. For example, VDCC (Ca_V1.2 channel), ryanodine receptor (RyR), Ca²⁺-dependent enzymes (Ca²⁺/CaM-dependent kinase [CaMK], calcineurin [CaN], and calpain), and scaffolding proteins (A-kinase anchoring proteins [AKAPs], caveolin, and junctophilin). Next, we discuss the roles of Ca²⁺ microdomain-based E-T coupling in physiological and pathophysiological remodeling in cardiac myocytes and vascular smooth muscle cells.

Keywords: Ca2+ microdomain; Ca2+ signaling; Cardiac myocyte; Excitation-transcription coupling; Vascular smooth muscle cell.

Fig. 1

E-T Coupling in Cardiac myocytes. A AKAP5 localized in the T-tubules of cardiac myocytes cooperates with Cav3 to form complexes with Ca_V1.2 channels, β-AR, AC, PKA, and CaN, leading to activation of the CaN/NFAT pathway and contributing to cardiac hypertrophy. Activation of CaMKIIδB via dephosphorylation by CaN activates CREB, inducing MCU expression and exerting cardioprotective effects. B Junctophilin 2 (Jph2) which tethers the T-tubules and SR is cleaved by calpain activated by sustained [Ca²⁺]_cyt elevation. Jph2-NT, generated by calpain-1, has a cardioprotective effect. In contrast, Jph2-CT, generated by calpain-2, is involved in cardiac hypertrophy. C Pressure overload and/or maintained neurohormonal stimulation increase both [Ca²⁺]_cyt and [Ca²⁺]_nuc. Calpain translocates CaN to the nucleus, and activates NFAT. This results in an increase in IP₃R expression levels, and further enhances [Ca²⁺]_nuc elevation. D Under chronic stimulation, CaMKIIδC accumulates in the perinuclear region and the nucleus, which promotes nuclear export of HDAC4, and thus activates MEF2. This can contribute to pathological remodeling. Furthermore, mAKAP on the nuclear membrane forms complexes with PKA, AC, and CaN, enhancing perinuclear Ca²⁺ signaling via RyR phosphorylation and activating the CaN/NFAT and CaN/MEF2 pathways, resulting in cardiac remodeling. AC: adenylyl cyclase, CaN: calcineurin, Cav3: caveolin 3, HDAC4: histone deacetylase 4, Jph2: junctophilin 2, Jph2-CT: C-terminal fragment of junctophilin 2, Jph2-NT: N-terminal fragment of junctophilin 2, mAKAP: muscle-specific A-kinase anchoring protein, MCU: mitochondrial Ca²⁺ uniporter, RyR: ryanodine receptor, SR: sarcoplasmic, β-AR: β-adrenergic receptor

Fig. 2

E-T coupling in vascular smooth muscle cells. A Phosphorylation of Ca_V1.2 channel by AT1R/PKC or P2Y11/PKA increases Ca_V1.2 channel clustering as well as co-operative interactions of these channels. NFAT translocates to the nucleus via dephosphorylation by CaN anchored to AKAP5. Agonist stimulation or pressure loading suppresses JNK2, stabilizing NFAT nuclear localization. Nuclear NFAT downregulates the expression of both BK_Ca subunits and Kv2.1, enhancing membrane depolarization. B Ca²⁺ influx mediated by Ca_V1.2 channels clustered in caveolae activates CaMKK2/CaMKI in a spatially localized fashion. CaMKI, phosphorylated by CaMKK2, translocates to the nucleus and activates CREB, where it may induce genes that produce pro-inflammatory products (e.g., cytokines and chemokines). AT1R: Angiotensin II type 1 receptor, BK_Ca: Large conductance Ca²⁺-activated K⁺ channel, CaN: calcineurin, Cav1: caveolin 1, JNK2: c-Jun N-terminal kinase 2, P2Y₁₁: P2Y purinoreceptor 11, PM: plasma membrane