Abstract
Connexin43 (Cx43) is the most ubiquitous gap junction protein in the human body and is essential for cell-to-cell communication in a variety of organs and organ systems. As a result, Cx43 is responsible for mediating both electrical and chemical signals, passing dissolved solutes and small signaling molecules between cells in a coordinated fashion. Here, we explore the electrophysiological properties of hemichannels formed from Cx43 and Cx43 fused to eGFP (Cx43eGFP) and their interactions in a planar lipid membrane (BLM). Unlike in vivo patch clamp experiments, Cx43 was purified and isolated from other membrane constituents allowing elucidation of individual protein responses to various electrical and chemical stimuli. Using this system, we examined hemichannel electrophysiology and the roles of several well-known gap junction blockers, namely: lanthanum, heptanol, carbenoxalone and lindane. We also observed a critical number of hemichannels required for an accelerated conductance increase, an emergent electrical signature indicative of plaque formation.
Highlights
Cx43 has an essential role in cellular communication in a variety of tissues [1,2]
When considering the amount of silently incorporated Cx43, the observation that the critical numbers of hemichannels required for both opposed and unopposed plaque formation is similar suggests that initial clustering may begin as an independent cellular process
Cellular adhesion machinery facilitates clustering at cell to cell contact points by reducing the surface area available for lateral diffusion [37], making unopposed plaque formation unlikely
Summary
Cx43 has an essential role in cellular communication in a variety of tissues [1,2]. Gap junction communication between two connexons is limited to molecules less than 1 kD, and single, unopposed hemichannels have been linked to a number of cellular processes including calcium waves, release of NAD+ and ATP, neuronal signaling, and the activation of several kinase cascades [3,4].Perhaps one of the most important functional aspects of gap junctions is the way the hexamer senses voltage and responds to it. Each hemichannel of a gap junction has its own voltage sensor, and several mutagenesis studies have shown that this voltage sensing is the cumulative effect of hemichannel subunit interactions [5,6,7,8,9]. It is how these interactions affect the partnering hemichannel which determines conductance and voltage gating properties of the gap junction. It is the emergent electrical properties of assembled elemental connexin which determine the gap junction’s voltage sensitivity. There is considerable variety in the intercellular communication requirements for various organs, it is not surprising that there is a large diversity in connexin molecular weight and subunit assembly [10]
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