Knowledge on the function of Connexin-43 on macrophages is gradually increasing and recent studies show how macrophages utilise Connexin-43. Migration, antigen-presentation and some forms of intercellular communication in macrophages are Connexin-43-dependant. Delicate processes, such as electrochemical support in conduction of the heartbeat in the AV-node, immunomodulatory regulation in the lungs and macrophage-differentiation are performed using Connexin-43 in macrophages. The relevance on pathophysiology becomes evident in inflammatory bowel disease, tumour networks and HIV in which aberrant function of Connexin-43 has been observed. Although many physiological, as well as pathophysiological functions were found to be Connexin-43-dependant, some still remain debated: the involvement of Connexin-43 in phagocytosis and polarisation, as well as its involvement in the mortality in murine sepsis are still unclear. These functions as well as further involvement in increasingly complex functions of the macrophage pose possible fields of research.

Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and tissue-specific and may be mediated by complex signalling pathways through gap junctions or hemichannels or by completely junction-independent events. Lung cancer is the number one cancer in terms of mortality worldwide, and novel biomarkers and therapeutic targets are urgently needed. Our objective was to gain a better understanding of connexins in this setting. We used several in silico tools to analyse TCGA data in order to compare connexin mRNA expression between healthy lung tissue and lung tumours and correlated these results with gene methylation patterns. Using Kaplan-Meier plotter tools, we analysed a microarray dataset and an RNA-seq dataset of non-small cell lung tumours in order to correlate connexin expression with patient prognosis. We found that connexin mRNA expression is frequently either upregulated or downregulated in lung tumours. This correlated with both good and poor prognosis (overall survival) in a clear connexin isoform-dependent manner. These associations were strongly influenced by the histological subtype (adenocarcinoma versus squamous cell carcinoma). We present an overview of all connexins but particularly focus on four isoforms implicated in lung cancer: Cx26, Cx30.3, Cx32 and Cx43. We further analysed the protein expression and localization of Cx43 in a series of 72 human lung tumours. We identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival (p=0.014). Upon sub-stratification, the prognostic value remained highly significant in the adenocarcinoma subtype (p=0.002) but not in the squamous carcinoma subtype (p=0.578). This finding highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. Elucidation of the underlying pathways regulating Cx43 localization may provide for novel therapeutic opportunities.

Connexins are tetraspan transmembrane proteins that form gap junctions and facilitate direct intercellular communication, a critical feature for the development, function and homeostasis of tissues and organs. In addition, a growing number of gap junction-independent functions are being ascribed to these proteins. The connexin gene family is under extensive regulation at the transcriptional and post-transcriptional level, and undergoes numerous modifications at the protein level, including phosphorylation, which ultimately affects their trafficking, stability and function. Here, we summarize these key regulatory events, with emphasis on how these affect their multi-functionality in health and disease.

Tunicate orthologs in the human genome comprise just 84 genes of the 19,872 protein-coding genes, yet they stand at the base of the Olfactores clade - which radiated to generate thousands of tunicate and vertebrate species. What were the powerful drivers among the 84 that enabled this process? Many of these orthologs are present in gene families. We discuss the biological role of each family and the orthologs’ quantitative contribution to the family. Most important was the evolution of a second type of cadherin. This, a Type II cadherin, had the property of detaching the cell containing that cadherin from cells that expressed the Type I class. The set of such Type II cadherins could now detach and move away from their Type I neighbours, a process which would eventually evolve into the formation of the neural crest, “ the fourth germ layer”, providing a wide range of possibilities for further evolutionary invention. A second important contribution were key additions to the broad development of the muscle and nerve protein and visual perception tool-kits. These developments in mobility and vision provided the basis for the development of the efficient predatory capabilities of the Vertebrata.

The modern paradigm of studying the processes of carcinogenesis and vital activity of tumor tissues implies increased attention to constituents of tumor microenvironment (TME) and their interactions. These interactions between the cells in TME can be mediated via protein junctions of different types. Connexins (Cnxs) are one of the major contributors to intercellular communication. They form gap junctions responsible for the transfer of ions, metabolites, peptides, miRNA, etc. between neighboring tumor cells as well as between tumor and stromal cells. Cnx hemichannels mediate purinergic signaling and bidirectional molecular transport with the extracellular environment. Additionally, Cnxs were reported to localize in tumor-derived exosomes and facilitate the release of their cargo. A large body of evidence implies that the role of connexins in cancer is multifaceted. Pro- or anti-tumorigenic properties of connexins are determined by their abundance, localization and functionality as well as channel assembly and non-channel functions. In this review we have summarized the data on the Cnxs contribution in TME and to the cancer initiation and progression.

Electrical transmission between neurons is largely mediated by gap junctions. These junctions allow the direct flow of electric current between neurons, and in mammals are mostly composed of the protein connexin (Cx)36. Circuits of electrically coupled neurons are widespread in these animals, plus, experimental and theoretical evidence supports the notion that, beyond synchronicity, these circuits are able to perform sophisticated operations like lateral excitation and inhibition, noise reduction, as well as the ability to selectively respond upon coincident excitatory inputs. Although once considered stereotyped and unmodifiable, we now know that electrical synapses are subject to modulation and, by reconfiguring neural circuits, these modulations can alter relevant operations. The strength of electrical synapses depends on gap junction conductance, as well as on its functional interaction with the electrophysiological properties of coupled neurons. In particular, voltage dependent channels of the non-synaptic membrane critically determine the efficacy of transmission at these contacts. Consistently, modulatory actions on these channels have been shown to represent relevant mechanisms of plasticity of electrical synaptic transmission. Here we review recent evidence on the regulation of electrical synapses of mammals, the underlying molecular mechanisms, and the possible ways in which they affect circuit function.