Regulation of Connexin Gap Junctions and Hemichannels by Calcium and Calcium Binding Protein Calmodulin

Abstract

Connexins are the structural components of gap junctions and hemichannels that mediate the communication and exchange of small molecules between cells, and between the intracellular and extracellular environment, respectively. Connexin (Cx) 46 is predominately expressed in lens fiber cells, where they function in maintaining the homeostasis and transparency of the lens. Cx46 mutations are associated with impairment of channel function, which results in the development of congenital cataracts. Cx46 gap junctions and hemichannels are closely regulated by multiple mechanisms. Key regulators of Cx46 channel function include Ca2+ and calmodulin (CaM). Ca2+ plays an essential role in lens homeostasis, and its dysregulation causes cataracts. Ca2+ associated CaM is a well-established inhibitor of gap junction coupling. Recent studies suggest that elevated intracellular Ca2+ activates Cx hemichannels in lens fiber cells and Cx46 directly interacts with CaM. A Cx46 site mutation (Cx46-G143R), which is associated with congenital Coppock cataracts, shows an increased Cx46-CaM interaction and this interaction is insensitive to Ca2+, given that depletion of Ca2+ reduces the interaction between CaM and wild-type Cx46. Moreover, inhibition of CaM function greatly reduces the hemichannel activity in the Cx46 G143R mutant. These research findings suggest a new regulatory mechanism by which enhanced association of Cx46 with CaM leads to the increase in hemichannel activity and dysregulation may lead to cataract development. In this review, we will first discuss the involvement of Ca2+/CaM in lens homeostasis and pathology, and follow by providing a general overview of Ca2+/CaM in the regulation of Cx46 gap junctions. We discuss the most recent studies concerning the molecular mechanism of Ca2+/CaM in regulating Cx46 hemichannels. Finally, we will offer perspectives of the impacts of Ca2+/CaM and dysregulation on Cx46 channels and vice versa.

Quantitative X-ray tomographic analysis reveals calcium precipitation in cataractogenesis

“…Recent studies have reported that Alizarin red-stained calcium precipitates are correlated with the morphology of nuclear opacity in mouse Cx46fs380 homozygous mutant lenses 38 ; the Cx50D47A mutant lenses show a similar distribution in the lens core with enriched calcium precipitates in the anterior Y-suture regions 39 . Connexin mutations disrupt calcium homeostasis and cause biomineralization in cataract formation 40 , 41 . This work indicates that age-related progression of Cx46KO nuclear cataracts is correlated with the age-related increase of calcium precipitates in Cx46KO lens cores, especially in the anterior Y-suture regions.…”

An Update on Connexin Gap Junction and Hemichannels in Diabetic Retinopathy

“…Opening of HCs is modified by connexin phosphorylation or by intracellular Ca 2+ concentrations [ 110 , 115 , 116 ]. In fact, moderate increments in intracellular Ca 2+ can promote HC opening by direct or indirect mechanisms, such as direct Ca 2+ /Calmodulin binding to Cx43 or by the activation of protein kinases [ 118 ]. More often, HCs are activated under pathological conditions, including oxidative stress, mechanical stretch, inflammatory processes, and lower pH.…”

Role and Posttranslational Regulation of Cx46 Hemichannels and Gap Junction Channels in the Eye Lens

“…It has been reported that Cx46 in the lens interacts with Ca 2+ -calmodulin (CaM) and that a Cx46 mutant (G143R) associated with cataracts in humans enhances the Cx46-CaM interaction and forms gap junction channels and hemichannels with altered voltage gating and permeability ( Hu et al, 2018 ). From these results, it has been suggested that the alteration in Cx46-CaM interaction can mediate the deleterious effect of some Cx46 mutations in lens fiber cells ( Figure 3 ) ( Hu et al, 2020 ).…”