Intracellular trafficking pathways of Cx43 gap junction channels

Abstract

Gap Junction (GJ) channels, including the most common Connexin 43 (Cx43), have fundamental roles in excitable tissues by facilitating rapid transmission of action potentials between adjacent cells. For instance, synchronization during each heartbeat is regulated by these ion channels at the cardiomyocyte cell-cell border. Cx43 protein has a short half-life, and rapid synthesis and timely delivery of those proteins to particular subdomains are crucial for the cellular organization of gap junctions and maintenance of intracellular coupling. Impairment in gap junction trafficking contributes to dangerous complications in diseased hearts such as the arrhythmias of sudden cardiac death. Of recent interest are the protein-protein interactions with the Cx43 carboxy-terminus. These interactions have significant impact on the full length Cx43 lifecycle and also contribute to trafficking of Cx43 as well as possibly other functions. We are learning that many of the known non-canonical roles of Cx43 can be attributed to the recently identified six endogenous Cx43 truncated isoforms which are produced by internal translation. In general, alternative translation is a new leading edge for proteome expansion and therapeutic drug development. This review highlights recent mechanisms identified in the trafficking of gap junction channels, involvement of other proteins contributing to the delivery of channels to the cell-cell border, and understanding of possible roles of the newly discovered alternatively translated isoforms in Cx43 biology. This article is part of a Special Issue entitled: Gap Junction Proteins edited by Jean Claude Herve.

Connexin 43 Mutations Lead to Increased Hemichannel Functionality in Skin Disease

“…In non-excitable tissue, gap junctions are involved in many physiological events, including cell differentiation, synchronization, and immune response [1][2][3][4]. This specialized intercellular coupling can also be found in excitable tissue, such as cardiac myocytes, where processes including rapid synchronization and facilitation of action potential propagation occur [5]. It is commonly known that gap junction channels are the only intercellular communication pathways that exclude the extracellular space, and are produced by the joining of adjacent connexin (Cx) channels in chordates [2,[6][7][8][9].…”

Understanding the Molecular and Cell Biological Mechanisms of Electrical Synapse Formation

“…Invertebrates accomplish the same task by using an evolutionarily distinct class of proteins called Innexins to form gap junctions (reviewed in Phelan, 2005;Güiza et al, 2018). Much like the CAMs at adherens and tight junctions, Connexins are intracellularly connected to scaffolding and cytoskeletal linkage proteins including ZO proteins and EB1 (Li et al, 2004;Epifantseva and Shaw, 2018). Thus, while there is some molecular overlap, each junction's unique morphology and function requires specialized membrane proteins, and fundamentally each must have a form of CAM, a scaffold, and an anchor to the cytoskeleton.…”

“…Most of our understanding of Connexin trafficking comes from studies of Cx43-based gap junctions (reviewed in Epifantseva and Shaw, 2018). In essence, Cx43 hemichannels are packaged into vesicles, travel along microtubules to an adherens junction situated near an established gap junction plaque, and are deposited into the membrane where they then migrate to and are incorporated into the plaque.…”

The interplay between electrical and chemical synaptogenesis

“…Cx43, one of the most commonly occurring connexins, is important for diverse functions such as the propagation of the cardiac action potential for synchronizing heartbeat, the coordinated contractions of uterine smooth muscles during birth, and the coupling of astrocytes in the brain ( Goodenough and Paul 2009 ; Tong et al 2009 ). The synthesis and trafficking of Cx43 have been well studied in these cell types ( Epifantseva and Shaw 2018 ). From these studies in vitro and in vivo, it is now known that this process involves the rapid transcription and accumulation of Cx43 mRNA in the cytoplasm, translation of the mRNA to protein in the rough endoplasmic reticulum, trafficking to the Golgi and assembly into connexons, vesicular transport along actin microfilaments and microtubules, insertion into the plasma membrane, and, finally, docking to cognate hemichannels at gap junctional plaques.…”