Connexon

Connexons play an imperative role in behavior and neurophysiology. Many of the details surrounding their pathological functions remain unknown as research has only begun recently. In the central nervous system (CNS), connexons play a major role in conditions such as epilepsy, ischemia, inflammation, and neurodegeneration.[1] The molecular mechanism as to how connexons play a role in the conditions listed above has yet to be fully understood and is under further research. Along with their key role in the CNS, connexons are crucial in the functioning of cardiac tissues. The direct connection allows for quick and synchronized firing of neurons in the heart which explains the ability for the heart to beat quickly and change its rate in response to certain stimuli.[2] Connexons also play an essential role in cell development. Specifically, their role in neurogenesis dealing with brain development as well as brain repair during certain diseases/pathologies and also assisting in both cell division as well as cell proliferation. The mechanism by which connexons aid in these processes is still being researched however, it is currently understood that this mechanism involves purinergic signaling (form of extracellular signaling mediated by purine nucleotides and nucleosides such as adenosine and ATP) and permeability to ATP.[1] Other important roles of connexons are glucose sensing and signal transduction. Connexons cause changes in extracellular glucose concentrations affecting feeding/satiety behavior, sleep-wake cycles, and energy use.[1] Further studies indicate that there is an increase in glucose uptake mediated by connexons (whose mechanism is still not fully understood) and under times of high stress and inflammation.[1] Recent research also indicates that connexons may affect synaptic plasticity, learning, memory, vision, and sensorimotor gating.

Some of the diseases associated with connexons are cardiovascular disease and diabetes, which is the inability of the body to produce insulin for glucose uptake by cells and degradation in the smaller units of connexons, called connexins, possibly leading to the onset of heart disease. Cardiovascular disease and diabetes, type I and II, affects similar locations within cells of the heart and pancreas. This location is the gap junction, where connexons facilitate rapid cell-to-cell interactions via electrical transmissions. Gap junctions are often present at nerve endings such as in cardiac muscle and are important in maintaining homeostasis in the liver and proper function of the kidneys. The gap junction itself is a structure that is a specialized transmembrane protein formed by a connexon hemichannel.[8] Cardiovascular disease and possibly type I and II diabetes, are each associated with a major protein connexin that makes up the gap junction.

In cardiovascular disease, Cx43 (connexin 43), a subunit of a connexon, is a general protein of the gap junction stimulating cardio myocyte muscle cells of intercalated discs facilitating synchronized beating of the heart. In the occurrence of cardiovascular disease the Cx43 subunit begins to show signs of oxidative stress, the ability of the heart to counteract the buildup of harmful toxins due to age or diet leading to reduced vascular functions.[8] Additionally, reduced Cx43 expression in vascular tissue, which plays a part in ventricular remolding and healing of wounds after a myocardial infarction, are present in structural heart disease.[9] However, the mechanisms of Cx43 in the heart are still poorly understood.[9] Overall, these changes in Cx43 expression and oxidant stress can lead to abnormalities in the coordinated beating of the heart, predisposing it to cardiac arrhythmias.[8]

Connexons are also associated with both Type I and Type II diabetes. Cx36 (connexin 36) subunit mediates insulin excretion and glucose-induced insulin release from gap junctions of the liver and pancreas.[4] Homeostasis in the liver and pancreatic organs are supported by an intricate system of cellular interactions called endocrine signaling. The secretion of hormones into the blood stream to target distant organs. However, endocrine signaling in the pancreas and liver operates along short distances in the cellular membrane by way of signaling pathways, ion channels, G-protein coupled receptors, tyrosine-kinase receptors, and cell-to-cell contact.[4] The gap junctions in these tissues supported by endocrine signaling arbitrate intracellular signals between cells and larger organ systems by connecting adjacent cells to each other in a tight fit. The Tight fit of the gap junction is such that cells in the tissue can communicate more efficiently and maintain homeostasis. Thus the purpose of the gap junction is to regulate the passage of ions, nutrients, metabolites, second messengers, and small biological molecules.[4] In diabetes the subsequent loss or degradation of Cx36 substantially inhibits insulin production in the pancreas and glucose in the liver which is vital for the production of energy for the entire body. A deficiency of Cx36 adversely affects the ability of the gap junction to operate within these tissues leading a reduction in function and possible disease. Similar symptoms associated with the loss or degradation of the gap junction have been observed in type II diabetes, however, the function of Cx36 in Type 1 and type II diabetes in humans is still unknown. Additionally, the Cx36 connexin is coded for by GJD2 gene, which has a predisposition on the gene locus for type II diabetes, and diabetic syndrome.[4]

• Andrew L Harris and Darren Locke (2009). Connexins, A Guide. New York: Springer. p. 574. ISBN 978-1-934115-46-6.