Gap Junction Channelopathies and Calmodulinopathies. Do Disease-Causing Calmodulin Mutants Affect Direct Cell-Cell Communication?

Camillo Peracchia

doi:10.3390/ijms22179169

Abstract

The cloning of connexins cDNA opened the way to the field of gap junction channelopathies. Thus far, at least 35 genetic diseases, resulting from mutations of 11 different connexin genes, are known to cause numerous structural and functional defects in the central and peripheral nervous system as well as in the heart, skin, eyes, teeth, ears, bone, hair, nails and lymphatic system. While all of these diseases are due to connexin mutations, minimal attention has been paid to the potential diseases of cell–cell communication caused by mutations of Cx-associated molecules. An important Cx accessory protein is calmodulin (CaM), which is the major regulator of gap junction channel gating and a molecule relevant to gap junction formation. Recently, diseases caused by CaM mutations (calmodulinopathies) have been identified, but thus far calmodulinopathy studies have not considered the potential effect of CaM mutations on gap junction function. The major goal of this review is to raise awareness on the likely role of CaM mutations in defects of gap junction mediated cell communication. Our studies have demonstrated that certain CaM mutants affect gap junction channel gating or expression, so it would not be surprising to learn that CaM mutations known to cause diseases also affect cell communication mediated by gap junction channels.

Highlights

In most tissues, neighboring cells share charged and neutral molecules of low molecular weight via cell–cell channels clustered at gap junction membranes
In addition to activating numerous enzymes, CaM is involved in the function of a growing family of membrane channels that, in addition to connexins/innexins channels, includes voltage-gated Ca2+ channels (CaV1.2), Na+ channels (Nav1.5), and K+ channels KV7.1(KCNQ1) and KV11.1 (KCNH2); small conductance Ca2+-activated K+ channels (SK); inwardly rectifying K+ channels (Kir, IRK); cyclic nucleotide-gated channels (CNG); ryanodine receptor (RyR2); transient receptor potential channels (TRP) [76,77,78]; and the water channel aquaporin-0 (AQP0), known as the eye lens protein MIP26 [79,80,81], the CaM binding site of which at the COOH-terminus we identified in the mid-1980s [82]
Most of the research on diseases caused by defects of direct cell–cell communication via gap junction channels has focused on connexin mutants

Summary

Introduction

In most tissues, neighboring cells share charged and neutral molecules of low molecular weight via cell–cell channels clustered at gap junction membranes. This form of direct cell–cell communication enables tissues to coordinate many cellular activities [1,2]. The potential role of CaM mutations in cell–cell communication has not been addressed This is not surprising since, until recently, no one expected that mutations of GENE GJA1 GJA3 GJA4 GJA5 GJA8 GJB1. Much to our surprise, in the past few years several diseases caused by CaM mutations (calmodulinopathies) have been identified [19] None of these calmodulinopathy studies, has considered the potential effect of CaM mutations on gap junction function. This review is intended to raise awareness of the potential effect of CaM mutations (and CaM mutations yet to be discovered) on direct cell–cell communication

Gap Junction Channelopathies

Does Calmodulin Play a Role in Gap Junction Channelopathies?

Calmodulinopathies

Do Calmodulin Mutants Affect Gap Junction Channel Function?

Expression of the CaM Mutants CaMCC or CaMNN

Conclusions and Future Perspective