Interactions of connexins with other membrane channels and transporters

Abstract

Cell-to-cell communication through gap junctions exists in most animal cells and is essential for many important biological processes including rapid transmission of electric signals to coordinate contraction of cardiac and smooth muscle, the intercellular propagation of Ca 2+ waves and synchronization of physiological processes between adjacent cells within a tissue. Recent studies have shown that connexins can have either direct or indirect interactions with other plasma membrane ion channels or membrane transport proteins with important functional consequences. For example, in tissues most severely affected by cystic fibrosis, activation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) has been shown to influence connexin function. Moreover, a direct interaction between Cx45.6 and the Major Intrinsic Protein/AQP0 in lens appears to influence the process of cell differentiation whereas interactions between aquaporin 4 (AQP4) and Cx43 in mouse astrocytes may coordinate the intercellular movement of ions and water between astrocytes. In this review, we discuss evidence supporting interactions between connexins and membrane channels/ transporters including CFTR, aquaporins, ionotropic glutamate receptors, and between pannexin1, another class of putative gap-junction-forming proteins, and Kvβ3, a regulatory β-subunit of voltage gated potassium channels. Although the precise molecular nature of these interactions has yet to be defined, their consequences may be critical for normal tissue homeostasis.

Interacting Network of the Gap Junction (GJ) Protein Connexin43 (Cx43) is Modulated by Ischemia and Reperfusion in the Heart*

“…Previous studies also demonstrated the functional interplay between Cx43/ Cx45 with other ABC transporters, namely with cystic fibrosis transmembrane conductance regulator (CFTR). Indeed, it was shown that GJIC can be regulated by CFTR through modulation of voltage sensitivity and gating of Cx channels (47). Although the molecular mechanisms involved are still unclear, it is known that CFTR/GJ crosstalk relies on a complex signaling network, involving c-src.…”

Prostaglandin E2 Regulation of Cystic Fibrosis Transmembrane Conductance Regulator Activity and Airway Surface Liquid Volume Requires Gap Junctional Communication

“…In addition, the inhibition of CFTR by ATP depletion abolished GJIC, whereas the activation of CFTR by cAMP opened gap junction channels within minutes (37,38). Therefore, a reciprocal regulation of the activity of the two channels occurs, and interestingly, the gating of gap junctions is impaired in CF epithelial cells (21). Regarding the importance of gap junctions in integrating multiple signaling pathways for the regulation of ASL volume, and thus the maintenance of a proper epithelial host defense, the altered regulation of GJIC may represent an additional layer of dysfunction in airway diseases.…”

“…In this context, gap junctions may contribute to the coordination of intercellular signaling, because they provide direct aqueous pores between neighboring cells, thus allowing the intercellular spread of ions, nucleotides, and second messengers (20). Gap junctions are present in airway epithelial cells, and the regulation of their channel activity is defective in CF (21,22). Thus, this study set out to determine whether gap junctions mediate the GPCR-induced activation of CFTR, and if their blockade could inhibit ASL volume homeostasis.…”

“…The activation of PAR involves the enzymatic cleavage of the NH2-terminus by proteases such as thrombin, trypsin, or elastase. After PAR stimulation, G proteins stimulate phospholipase C-b to produce inositol 1,4, 5-trisphosphate, which in turn increases intracellular Ca 21 concentrations and PKC activity. The activation of PAR in the basal membrane by trypsin or with PAR-2-selective peptides was shown to regulate ion transport function in airway epithelial cells (10,11).…”

14-3-3θ Facilitates plasma membrane delivery and function of mechanosensitive connexin 43 hemichannels

“…The interaction of Cx43 with other proteins is gaining considerable importance for their role in the regulation of Cx43 trafficking, assembly and disassembly as well as the dynamic modulation of channel opening (Chanson et al, 2007;Hervé et al, 2007). Although, 14-3-3 has been shown to interact with several integrins including b1, aLb2 and a4 (Deakin et al, 2009;Han et al, 2001;Nurmi et al, 2006), our study is the first to show that 14-3-3h interacts with integrin a5.…”