br Gap junctions hemichannels and connexins

Gap junctions, hemichannels and connexins: Molecular characteristics and function Cell-to-cell communication is of extreme importance in tissue homeostasis, which is maintained by transmission of regulatory signals (Fig. 1). Intercellular communication via gap junctions (GJs) represents one of the most important routes of rapid signalling between cells. GJ channels span 2 plasma membranes and consist of 2 hemichannels (connexons), one belonging to each cell. Each hemichannel is formed by 6 connexin (Cx) subunits and is permeable to small molecules up to 1–1.5kD. They serve to provide electrical and chemical conductance as well as metabolic assistance.[2], [3] GJ communication is modulated by many factors such as cytokines, growth factors and nitric oxide (NO), making them susceptible to change during cell stress and injury.[4], [5] Cxs consist of 4 transmembrane helices (M1-M4). The N- and C-terminal ends are intracellular. The primary sequence of the intracellular loop is not well conserved, while the C-terminal sequence varies a lot between Cxs with Cx26 being ∼20 Ketoconazole and Cx43 being 150 amino acids long. More than 20 Cxs have been identified with different molecular weights and their expression patterns vary between cell types and tissues. Many different Cxs have been observed in the liver. Endothelial cells, Kupffer cells and stellate cells mainly express Cx43, hepatocytes express Cx32 and to a lesser extent Cx26, while liver vascular cells express Cx37 and Cx40 (Fig. 2).[2], [7], [8], [9] Across Cxs isoforms, there is a wide variation in conductance (most hemichannels have a fixed negative charge in the pore making them cation selective) and permeability characteristics that have likely evolved according to the requirements of the tissue in which they are expressed. Moreover, their plasticity allows them to compensate for the loss or downregulation of other Cxs as revealed by several knockout models. Furthermore, in these models, disturbed cell development has been observed, suggesting that GJs and hemichannels play an important role in processes such as migration, differentiation and proliferation. Cxs can also exist as functional hemichannels allowing the exchange of ions between the intra and the extracellular milieu.[2], [4] Under normal physiological conditions, hemichannels are either closed or in a flickering state. Maintaining controlled gating to allow entry or exit of molecules from the cell is very important to preserve normal cellular integrity and function. Therefore, hemichannels are constantly under the control of factors such as membrane potential, pH, post-translational modification (phosphorylation, ubiquitination, S-nitrosylation), mechanical stimulation and intracellular/extracellular calcium.[3], [12], [13] Facilitated opening of hemichannels has been shown to correlate with cell death in cerebral ischaemia, resulting in the loss of osmoregulation, excitotoxicity and the spread of inflammation. Although hemichannels and pannexins (structurally similar to Cx proteins) are also of great interest in liver disease, their role in liver disease will not be discussed in any detail in this review (for an extended review on liver pannexins see.).
Connexin and gap junction alterations in disease Cx protein mutations are associated with various diseases such as hearing loss, which is linked to Cx26 and Cx30, and atrial fibrillation which is associated with a Cx40 mutation.[16], [17] Additionally, under other pathological conditions, such as focal ischaemia, opening of GJs serves a protective role, enabling cells to save their compromised neighbours by providing essential molecules to areas of high demand. However, maintaining GJ communication in severely injured or diseased tissue areas allows the spread of toxic substances, propagating and worsening cell injury. The diseases associated with congenital or acquired Cx involvement are shown (Fig. 3). It is notable that none of the mutations described affect the liver.