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

Fereshteh Moradi,Emily N Copeland,Ryan W Baranowski,Jeffrey A Stuart,Val A Fajardo,Aiden E Scholey

doi:10.3390/ijms21031016

Fereshteh Moradi, Emily N Copeland + Show 4 more

Open Access

https://doi.org/10.3390/ijms21031016

Copy DOI

Journal: International journal of molecular sciences	Publication Date: Feb 4, 2020
Citations: 12	License type: CC BY 4.0

Affiliation: Brock University

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.

Highlights

Composed of two canonical EF-hand lobes, calmodulin (CaM) binds up to four Ca2+ ions
While these findings reveal the importance of nuclear receptor interacting protein (NRIP) in both systolic and diastolic function, no alterations in CaM-dependant kinase II (CaMKII) nor nuclear factor of activated T cells (NFAT) phosphorylation were observed, and unlike skeletal muscle, the impairments in cardiac contractility were not associated with changes in CaMKII or CaN activation
Given the importance of Ca2+ regulation and CaM signalling in cardiomyocytes, investigations focusing on the potential role of growth-associated protein 43 (GAP43) in cardiac muscle will be of interest

Summary

Introduction

Composed of two canonical EF-hand lobes, calmodulin (CaM) binds up to four Ca2+ ions. CaM can bind to and activate several proteins that regulate gene expression and Ca2+ handling, influencing muscle contractility, metabolism, and plasticity [2,3]. These include but are not limited to CaM-dependant kinase II (CaMKII), calcineurin (CaN), ryanodine receptor (RyR), and dihydropyridine receptor (DHPR) [3,4,5,6,7]. Proteins that contain the IQ motif are able to bind to CaM in its Ca2+-free (apo-CaM) and/or Ca2+-bound states These IQ motif proteins may regulate CaM availability at low and high Ca2+ levels by sequestering CaM away from its downstream targets, or facilitating its interaction with other proteins by concentrating CaM in localized pools. We discuss recent research revealing the physiological roles of three small IQ motif proteins in skeletal and cardiac muscle: nuclear receptor interacting protein (NRIP), growth-associated protein 43 (GAP43), and neurogranin (Ng)

Nuclear Receptor Interacting Protein

Neurogranin

Growth-Associated Protein 43

Physiological Significance

Findings

Conclusions