Calmodulin-Binding Proteins in Muscle: A Minireview on Nuclear Receptor Interacting Protein, Neurogranin, and Growth-Associated Protein 43

Abstract

Calmodulin (CaM) is an important Ca²⁺-sensing protein with numerous downstream targets that are either CaM-dependant or CaM-regulated. In muscle, CaM-dependent proteins, which are critical regulators of dynamic Ca²⁺ handling and contractility, include calcineurin (CaN), CaM-dependant kinase II (CaMKII), ryanodine receptor (RyR), and dihydropyridine receptor (DHPR). CaM-regulated targets include genes associated with oxidative metabolism, muscle plasticity, and repair. Despite its importance in muscle, the regulation of CaM-particularly its availability to bind to and activate downstream targets-is an emerging area of research. In this minireview, we discuss recent studies revealing the importance of small IQ motif proteins that bind to CaM to either facilitate (nuclear receptor interacting protein; NRIP) its activation of downstream targets, or sequester (neurogranin, Ng; and growth-associated protein 43, GAP43) CaM away from their downstream targets. Specifically, we discuss recent studies that have begun uncovering the physiological roles of NRIP, Ng, and GAP43 in skeletal and cardiac muscle, thereby highlighting the importance of endogenously expressed CaM-binding proteins and their regulation of CaM in muscle.

Keywords: CaMKII; GAP43; IQ-motif; NRIP; calcineurin; neurogranin; neuromodulin.

Figure 1

Simplified scheme of the physiological roles of calmodulin (CaM)-binding proteins, nuclear receptor interacting protein (NRIP), neurogranin (Ng), and growth-associated protein 43 (GAP43) in skeletal muscle. (A) CaM-binding proteins that facilitate CaM binding with its downstream targets leads to their subsequent activation (green arrows). Recent evidence has revealed a role for NRIP in facilitating CaM binding to ryanodine receptor (RyR) and dihydropyridine receptor (DHPR), thereby contributing to increased sarcoplasmic reticulum (SR) Ca²⁺ release [9]. NRIP also facilitates CaM binding and activation of CaMKII and CaN. Activated CaMKII phosphorylates class-II histone deacetylases (HDACs), thereby activating myocyte enhancer factor 2 (MEF2). CaN dephosphorylates nuclear factor of activated T-cell (NFAT), leading to its nuclear entry. Together MEF2 and NFAT increase the expression of genes associated with oxidative fibre type, fatigability, myogenic differentiation, myoblast fusion, and muscle regeneration [9]. The dashed green arrow illustrates the hypothetical scenario by which enhanced CaM-dependent kinase II (CaMKII) activation with NRIP can lead to increased SERCA-mediated Ca²⁺ uptake, thereby enhancing total SR Ca²⁺ potentially by phosphorylating phospholamban (not shown here) and relieving its inhibition of SERCA. (B) CaM binding proteins that sequester CaM away from its downstream targets lead to a subsequent reduction in their activation (red arrows). Ng binds to CaM and prevents its binding to CaN, leading to a reduction in myogenic differentiation, myoblast fusion, and utrophin expression [28]. GAP43 binds to CaM and prevents it from binding to RyR and DHPR, thereby reducing SR Ca²⁺ release. The role of NRIP in maintaining normal cardiac function [11] is not shown here.