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.

ERK1/2 inhibition promotes robust myotube growth via CaMKII activation resulting in myoblast-to-myotube fusion

“…Upon Ca 2+ /CaM binding to individual CaMKII subunits, cross-phosphorylation of neighboring subunits at T287 leads to a state of autonomous activation, by increasing the affinity for Ca 2+ /CaM several thousand-fold. Previously, CaMKII was identified for its role in Ca 2+ -dependent regulation of gene expression associated with muscle-oxidative metabolism, as well as components of the contractile machinery ( Eilers, 2014a , Eilers, 2014b , Moradi, 2020 , Ojuka, 2012 , Richter and Hargreaves, 2013 , Rose, 2007 ). However, to date, the specific role of CaMKII in the regulation of myoblast fusion has not been demonstrated.…”

Calcineurin

“…These encompass a broad range of proteins and enzymes. These include, but are not limited to, the previously-mentioned the CaM-modulated kinases [ 5 ], nitric oxide synthases [ 37 ], the calcium-release channel ryanodine receptors [ 38 ], proteins such as neurogranin and growth-associated protein-43 [ 39 ], and even the microtubule-associated protein tau [ 40 , 41 ]. Notably, CaM modulates the activities of enzymes such as CaN and the CaM-modulated kinases which are involved in numerous signaling processes.…”

The effects of neurogranin knockdown on SERCA pump efficiency in soleus muscles of female mice fed a high fat diet

“…Calcineurin, a Ca2+/calmodulin (CaM) dependent serine/ threonine phosphatase, has previously been shown to promote the slow-oxidative phenotype in skeletal muscle (1)(2)(3)(4)(5). More specifically, in the presence of intracellular Ca2+ ([Ca2+]i), CaM will be activated via a Ca2+/CaM complex that can interact with calcineurin, displacing its autoinhibitory domain, allowing for its activation (6).…”

“…Neurogranin (Ng) is a negative calcineurin regulator that we recently found to be expressed in skeletal muscle, specifically the soleus ( 21 ). Ng acts to reduce the availability of CaM to interact with calcineurin while also limiting the affinity of CaM for Ca2+, ultimately reducing the activation of calcineurin ( 5 , 21 – 26 ). In muscle, heterozygous reduction of Ng (Ng+/-) activates calcineurin signaling and promotes the slow-oxidative myogenic program and fatigue resistance ( 27 ).…”