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.