Connexins and Disease

Abstract

Inherited or acquired alterations in the structure and function of connexin proteins have long been associated with disease. In the present work, we review current knowledge on the role of connexins in diseases associated with the heart, nervous system, cochlea, and skin, as well as cancer and pleiotropic syndromes such as oculodentodigital dysplasia (ODDD). Although incomplete by virtue of space and the extent of the topic, this review emphasizes the fact that connexin function is not only associated with gap junction channel formation. As such, both canonical and noncanonical functions of connexins are fundamental components in the pathophysiology of multiple connexin related disorders, many of them highly debilitating and life threatening. Improved understanding of connexin biology has the potential to advance our understanding of mechanisms, diagnosis, and treatment of disease.

Figure 1.

Connexin structure and organization. Connexins have four transmembrane domains (TM1–4), two extracellular loops (E1–2), a cytoplasmic loop (CL), and cytoplasmic amino and carboxyl termini (NT and CT). Six connexins oligomerize to form a connexon, also known as a hemichannel, which dock with a connexon from a neighboring cell to form an intercellular gap junctional channel. Gap junctional channels form densely packed plaques that appear as a pentalaminar structure in electron microscopy (EM) (between arrows in left panel). Scalebar, 100 nm. (From Axelsen et al. 2013, reprinted, with permission, from the authors.)