Bioelectricity

Connexins, elementary protein units of gap junctions, make intercellular and membrane channels that work as conduits for ions and larger molecules >1 kDa. Electrically, cells well coupled by gap junctions display a relatively uniform resting potential. In excitable tissues, gap junctions are the pathway for electrotonic propagation of action potentials. When hemichannels open in the membrane, connecting the cytoplasm and the extracellular space, the resting potential could collapse, and action potential propagation be impaired. Because connexin channels are permeated by large molecules, gap junctions are assumed to synchronize cellular functions by the sharing of second messengers, metabolites, and other substances. In turn, hemichannel opening could allow the escape of those same substances, and the uptake of extracellular molecules. Separately from their channel function, parts of the connexin molecule can induce cellular changes that suggest protein-protein interactions with the cytoskeleton, regulatory pathways, and the genomic machinery of the cells. This minireview gives an overview of connexins and discusses some of the outstanding issues in the field.

Mutations of lens connexins are linked to congenital cataracts. However, the role of connexin mutations in the development of age-related lens opacification remains largely unknown. Here, we present a focused review of the literature on lens organization and factors associated with cataract development. Several lines of evidence indicate that disturbances of the lens circulation by dysfunctional connexin channels, and/or accumulation of protein damage due to oxidative stress, are key factors in cataract development. Phosphorylation by protein kinase A improves the permeability of connexins channels to small molecules and mitigates the lens clouding induced by oxidative stress. We conclude (1) that connexin channels are central to the lens circulation and (2) that their permeability to antioxidant molecules contributes to the maintenance of lens transparency.

The presence of gap junction intercellular communication structures in bone cells has been known since the early 1970s, further confirmed by Doty and Marotti at the structural level in the 1980–1990s. Work by Civitelli, Donahue, and others showed the expression of Cx43 at the mRNA and protein levels in all bone cell types: osteoclasts (bone resorbing cells), osteoblasts (bone forming cells), and osteocytes (mature osteoblasts embedded in the bone matrix that regulate the function of both osteoclasts and osteoblasts). While Cx45, Cx46, and Cx37 were also shown to be expressed in bone cells, most studies have focused on Cx43, the most abundant member of the connexin (Cx) family of proteins expressed in bone. The role of Cx43 has been shown to be related to the formation of gap junction intercellular channels, to unopposed hemichannels, and to channel independent functions of the molecule. Cx43 participates in the response of bone cells to pharmacological, hormonal, and mechanical stimuli, and it is involved in the skeletal phenotype with old age. Human and murine studies have shown that mutations of Cx43 lead to oculodentodigital dysplasia and craniometaphyseal dysplasia, both conditions associated with abnormalities in the skeleton. However, whereas substantial advances have been made on the skeletal role of Cx43, further research is needed to understand the basis for the effects of mutated Cx43 and potential ways to prevent the effects of these mutations on bone.

Developmental morphogenesis reliably builds species-specific large-scale anatomies. Crucially, regulative development and regeneration after diverse and unpredictable damage illustrate that groups of cells deploy context-sensitive, homeostatic algorithms that can navigate anatomical state space in flexible ways. While the molecular machinery necessary for this process is increasingly becoming characterized, the algorithms that guide growth and form are still poorly understood. To drive progress in regenerative medicine and bioengineering, constructive models need to be formulated and tested that show the kinds of information exchange sufficient for specific morphogenetic competencies. Here, we propose a computational model of planarian regeneration that relies on cell-cell communication via gap junction channels and the use of stress as a driver of homeostatic change. We simulate key experiments in the planarian model system and show that this framework is sufficient to demonstrate the observed regenerative behavior of planaria under bioelectric perturbation. This model suggests testable hypotheses in vivo, and it provides a framework for design strategies for control circuits in synthetic bioengineering.

For this special issue of Bioelectricity, I have focused on our early studies involving voltage sensitivity of gap junctions, stressing possible consequences for the establishment or maintenance of communication compartments during development. I also describe how the progressive new tools in those and subsequent studies have led to the realization that gap junction channels have connexin-specific properties and that confer upon them differential sensitivities to gating stimuli. Moreover, mutations in connexin sequences and posttranslational modifications can alter these intrinsic properties and their interaction with binding partners, contributing to pathological conditions. Numerous fundamental questions remain to be resolved, and the field badly needs highly potent and selective pharmacological reagents to distinguish nonjunctional connexin channels from other membrane pores.

The following is a report on the 19th World Congress of Basic & Clinical Pharmacology (WCP) meeting in Glasgow. We present our highlights of the various symposia, keynote lectures, workshops and debates. Our focus includes the “Ion Channel Pharmacology” symposium co-organised by Gary Stephens and which featured a talk by Professor Bill Catterall, who also received an IUPHAR Lifetime Achievement Award during the meeting. Further highlights relating to ion channels, receptors and new areas of drug discovery, amongst others, are discussed.