The contractile system as a negative regulator of the connexin 43 hemichannel

Abstract

The molecular mechanisms underlying the regulation of gap junction (GJ) channels based on the 43-kDa connexin isoform (Cx43) have been studied extensively. GJ channels are formed by the docking of opposed hemichannels in adjacent cells. Mounting data indicate that unopposed Cx43 hemichannels are also functional in the plasma membrane. However, our understanding of how Cx43-hemichannel opening and closing is regulated at the molecular level is only poorly understood. Recent work elucidated that actomyosin contractility inhibits potently Cx43 hemichannels. It is known that intracellular Ca2+ exerts a bell-shaped-dependent effect on Cx43-hemichannel opening. While low-intracellular [Ca2+] (<500 nM) provokes opening of the channel, high-intracellular [Ca2+] (> 500 nM) favours closing of the channel. The mechanism underlying this negative regulation of Cx43-hemichannel activity by high-intracellular [Ca2+] seems to be dependent on the activation of the actomyosin contractile system. The activity of Cx43 hemichannels is critically controlled by molecular interactions between the intracellular loop and the C-terminal tail. These interactions are essential for Cx43-hemichannel opening in response to triggers such as cytosolic [Ca2+] rise or external [Ca2+] lowering. In this review, we present the hypothesis that the actomyosin contractile system can function as an important brake mechanism on Cx43-hemichannel opening. By controlling loop-tail interactions, the contractile system would prevent aberrant or excessive opening of Cx43 hemichannels. Release of signalling molecules through connexin (Cx) hemichannels mediate local paracrine signalling. However, prolonged or aberrant opening of these hemichannels causes a collapse in energy, ion or metabolic gradients. Here, we discuss our recent findings on how contractility provides an endogenous brake that tightly controls the opening of the connexin 43-kDa hemichannel (Cx43), one of the most ubiquitously expressed Cx isoforms, and thus prevents excessive Cx43-hemichannel activity during physiological signalling. Our hypothesis is that contractility dislodges the C-terminal tail from the intracellular loop of Cx43 and thus interferes with intramolecular loop-tail interactions essential for Cx43-hemichannel activity. © 2012 Soçiété Francaise des Microscopies and Société de Biologie Cellulaire de France.