Connexins and Pannexins: Important Players in Neurodevelopment, Neurological Diseases, and Potential Therapeutics

Abstract

Cell-to-cell communication is essential for proper embryonic development and its dysfunction may lead to disease. Recent research has drawn attention to a new group of molecules called connexins (Cxs) and pannexins (Panxs). Cxs have been described for more than forty years as pivotal regulators of embryogenesis; however, the exact mechanism by which they provide this regulation has not been clearly elucidated. Consequently, Cxs and Panxs have been linked to congenital neurodegenerative diseases such as Charcot-Marie-Tooth disease and, more recently, chronic hemichannel opening has been associated with adult neurodegenerative diseases (e.g., Alzheimer’s disease). Cell-to-cell communication via gap junctions formed by hexameric assemblies of Cxs, known as connexons, is believed to be a crucial component in developmental regulation. As for Panxs, despite being topologically similar to Cxs, they predominantly seem to form channels connecting the cytoplasm to the extracellular space and, despite recent research into Panx1 (Pannexin 1) expression in different regions of the brain during the embryonic phase, it has been studied to a lesser degree. When it comes to the nervous system, Cxs and Panxs play an important role in early stages of neuronal development with a wide span of action ranging from cellular migration during early stages to neuronal differentiation and system circuitry formation. In this review, we describe the most recent available evidence regarding the molecular and structural aspects of Cx and Panx channels, their role in neurodevelopment, congenital and adult neurological diseases, and finally propose how pharmacological modulation of these channels could modify the pathogenesis of some diseases.

Gap Junctions and Connexins in Microglia-Related Oxidative Stress and Neuroinflammation: Perspectives for Drug Discovery

“…Moreover, in Huntington’s disease, increased Cx43 GJs have been related to the mitochondrial fragmentation deriving from the abnormally long polyglutamine found in the HTT protein [ 223 ]. Based on the above, Cxs and Panxs have been investigated as potential therapeutic targets in neurodegenerative disorders [ 225 ]. However, the limitation in the drug discovery processes stems from the fact that Cxs and Panxs are widely expressed in the CNS obscuring different physiological roles in strict dependence on their localization.…”

“…Concerning AD, the alkaloid boldine (derived from the boldo tree Peumus boldus ) has demonstrated a selective pharmacological activity in inhibiting astrocytic and microglial HCs, without affecting GJs. Its activity was tested in a murine model of AD and led to a reduction of ATP and glutamate release in the hippocampus, resulting in reduced neuronal degeneration [ 225 , 228 ]. Additionally, cannabinoids (CBs) have been shown to regulate the opening of GJs, HCs, and pannexons during neuroinflammation [ 217 , 229 ], particularly in neurons [ 205 ] and astrocytes-altered networks [ 230 , 231 , 232 ].…”