Calcium Signalling in Heart and Vessels: Role of Calmodulin and Downstream Calmodulin-Dependent Protein Kinases

Abstract

Cardiovascular disease is the major cause of death worldwide. The success of medication and other preventive measures introduced in the last century have not yet halted the epidemic of cardiovascular disease. Although the molecular mechanisms of the pathophysiology of the heart and vessels have been extensively studied, the burden of ischemic cardiovascular conditions has risen to become a top cause of morbidity and mortality. Calcium has important functions in the cardiovascular system. Calcium is involved in the mechanism of excitation-contraction coupling that regulates numerous events, ranging from the production of action potentials to the contraction of cardiomyocytes and vascular smooth muscle cells. Both in the heart and vessels, the rise of intracellular calcium is sensed by calmodulin, a protein that regulates and activates downstream kinases involved in regulating calcium signalling. Among them is the calcium calmodulin kinase family, which is involved in the regulation of cardiac functions. In this review, we present the current literature regarding the role of calcium/calmodulin pathways in the heart and vessels with the aim to summarize our mechanistic understanding of this process and to open novel avenues for research.

Keywords: calcium calmodulin dependent protein kinases; calcium signalling; calmodulin; cardiovascular disease.

Figure 1

Schematic representation of Ca²⁺-CaM activation. After binding 4 ions of Ca²⁺, calmodulin undergoes conformational change that leads to activation of downstream proteins.

Figure 2

The 3D illustrations show the flexibility of calmodulin in binding to 4 Ca²⁺ and undergoing conformational changes for its reaction with a specific downstream protein, such as the CaM kinase proteins. Specifically, the binding of the calcium–calmodulin complex to auto-inhibitory target protein regions leads this conformational change and the target protein activation. Ca²⁺ is displayed as yellow balls and peptide is shown as magenta ribbon.

Figure 3

The general structure shared by the CaM-kinases. The N-terminal catalytic domain is represented in light blue, followed by a regulatory region containing in white the autoinhibitory domain and in dark blue the CaM-binding domain. The black block shows the C-terminal association domain of CaMKII. Adapted from Beghi S, et al., 2020 [39].

Figure 4

Ca²⁺-CaM kinases downstream of calmodulin. Binding of calcium to calmodulin leads to activation of the Ca²⁺-CaM-dependent kinase cascade, consisting of CaMKK1 and CaMKK2, CaMKI, and CaMKIV, as well as activation of CaMKII. The activation of CaMKKs regulates crucial cellular functions. Calcium calmodulin mediates downstream signalling of CaMKI, CaMKIV, AMPK, Akt, and mTOR.