Plasma Membrane Channels Formed by Connexins: Their Regulation and Functions

Abstract

Members of the connexin gene family are integral membrane proteins that form hexamers called connexons. Most cells express two or more connexins. Open connexons found at the nonjunctional plasma membrane connect the cell interior with the extracellular milieu. They have been implicated in physiological functions including paracrine intercellular signaling and in induction of cell death under pathological conditions. Gap junction channels are formed by docking of two connexons and are found at cell-cell appositions. Gap junction channels are responsible for direct intercellular transfer of ions and small molecules including propagation of inositol trisphosphate-dependent calcium waves. They are involved in coordinating the electrical and metabolic responses of heterogeneous cells. New approaches have expanded our knowledge of channel structure and connexin biochemistry (e.g., protein trafficking/assembly, phosphorylation, and interactions with other connexins or other proteins). The physiological role of gap junctions in several tissues has been elucidated by the discovery of mutant connexins associated with genetic diseases and by the generation of mice with targeted ablation of specific connexin genes. The observed phenotypes range from specific tissue dysfunction to embryonic lethality.

Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function

“…Each Cx has its own tissue distribution and each cell, with a few exceptions, expresses one or more Cxs. Cx43, Cx40, Cx45 and Cx31 are found in the cardiomyocytes of the human heart 45,46 . Cx43 is the major ventricular Cx responsible for gap junction coupling in ventricles.…”

Key Connexin 43 Phosphorylation Events Regulate the Gap Junction Life Cycle

“…They coordinate cell-to-cell communication within tissues by allowing for the transfer of molecules less than 1000 Daltons between cells including ions, amino acids, nucleotides, second messengers (e.g., Ca 2+ , cAMP, cGMP, IP 3 ) and other metabolites (Loewenstein & Azarnia, 1988;Saez et al, 2003;Simon, Goodenough & Paul, 1998;Willecke et al, 2002). In vertebrates, gap junctions are composed of proteins from the connexin family, which is composed of 21 members in humans (Goodenough & Paul, 2003;Saez et al, 2003;Sohl & Willecke, 2004). Connexins are commonly designated with numerical suffixes referring to the molecular weight of the deduced sequence in kilodaltons (e.g., connexin43 or Cx43) (Saez et al, 2003;Sohl & Willecke, 2004).…”

“…In vertebrates, gap junctions are composed of proteins from the connexin family, which is composed of 21 members in humans (Goodenough & Paul, 2003;Saez et al, 2003;Sohl & Willecke, 2004). Connexins are commonly designated with numerical suffixes referring to the molecular weight of the deduced sequence in kilodaltons (e.g., connexin43 or Cx43) (Saez et al, 2003;Sohl & Willecke, 2004). Connexins are differentially expressed in tissues with some being significantly expressed in only a few tissues and some, like Cx43, being more widespread.…”

Inflammatory conditions induce gap junctional communication between rat Kupffer cells both in vivo and in vitro

“…A less explored communication pathway is that which is mediated by gap junctions. A few reports have demonstrated the presence of gap junctions in immune cells, including monocytes/ macrophages, microglia, polymorphonuclear cells, and dendritic cells (3). Nonetheless, the immune signals that regulates the expression of connexins (Cxs), protein subunits of gap junctions, and their role in KCs remains to be elucidated.…”

“…Gap junction channels are formed by two hemichannels or connexons; each connexon is a hexamer of Cxs that are encoded by a gene family (3). The expression of Cxs and properties of these channels are affected by numerous extracellular factors and post-transcriptional modifications in a Cx-and cell type-dependent manner (3).…”