Plasma membrane calcium ATPase proteins as novel regulators of signal transduction pathways

Abstract

Emerging evidence suggests that plasma membrane calcium ATPases (PMCAs) play a key role as regulators of calcium-triggered signal transduction pathways via interaction with partner proteins. PMCAs regulate these pathways by targeting specific proteins to cellular sub-domains where the levels of intracellular free calcium are kept low by the calcium ejection properties of PMCAs. According to this model, PMCAs have been shown to interact functionally with the calcium-sensitive proteins neuronal nitric oxide synthase, calmodulin-dependent serine protein kinase, calcineurin and endothelial nitric oxidase synthase. Transgenic animals with altered expression of PMCAs are being used to evaluate the physiological significance of these interactions. To date, PMCA interactions with calcium-dependent partner proteins have been demonstrated to play a crucial role in the pathophysiology of the cardiovascular system via regulation of the nitric oxide and calcineurin/nuclear factor of activated T cells pathways. This new evidence suggests that PMCAs play a more sophisticated role than the mere ejection of calcium from the cells, by acting as modulators of signaling transduction pathways.

Keywords: Calcineurin; Nitric oxide; Nuclear factor of activated T cells; Plasma membrane calcium ATPase; Regulation; Signal transduction.

Figure 1

Model of plasma membrane calcium ATPase (PMCA) as a regulator of signal transduction pathways. PMCA pumps calcium out of the cell and generates a microenvironment where the intracellular calcium concentrations are very low. Interaction with the intracellular domains of PMCA tethers partner proteins to this low-calcium microenvironment, which results in downregulation of the enzymatic activity of calcium/calmodulin-dependent proteins. Ca²⁺/CaM-dep, calcium/calmodulin-dependent enzyme.

Figure 2

Physiological consequences of the interaction between PMCAs and signaling partner proteins in the cardiovascular system. The figure depicts regulatory interactions between PMCA and calcium-dependent signaling proteins in cardiovascular cells. These interactions play a pivotal role in the regulation of cardiovascular physiology via regulation of the NO and calcineurin/NFAT signal transduction pathways. CnA: Calcineurin A; sGC: Soluble guanylyl cyclase; PDE: Phosphodiesterase; PKA: Protein kinase A; PBL: Phospholamban; cTn I: Cardiac troponin I; βAR: β-adrenergic receptor; AC: Adenylyl cyclase; NFAT: Nuclear factor of activated T cells.