Gap junction channel structure in the early 21st century: facts and fantasies

Yeager, Mark; Harris, Andrew L.

doi:10.1016/j.ceb.2007.09.001

Cited by 133 publications

(89 citation statements)

References 52 publications

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“…Consistent with changes in Cx43 folding that can accompany transport along the secretory pathway, conformation specific antibodies against the C terminus of Cx43 have been identified that specifically recognize either Golgi-or gap junction-localized Cx43 (Sosinsky et al, 2007). In particular, the fully formed connexin channel contains an aqueous pore lined by polar and charged amino acids from multiple connexin transmembrane domains (Yeager and Harris, 2007). Thus, the conformation Cx43 assumes when assembled into a hexamer is expected to be unstable for monomeric Cx43 because these polar residues would be exposed to the hydrophobic portion of the membrane instead of part of the aqueous pore.…”

Section: Discussionmentioning

confidence: 88%

ERp29 Restricts Connexin43 Oligomerization in the Endoplasmic Reticulum

Das

Smith

Sarma

et al. 2009

MBoC

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Connexin43 (Cx43) is a gap junction protein that forms multimeric channels that enable intercellular communication through the direct transfer of signals and metabolites. Although most multimeric protein complexes form in the endoplasmic reticulum (ER), Cx43 seems to exit from the ER as monomers and subsequently oligomerizes in the Golgi complex. This suggests that one or more protein chaperones inhibit premature Cx43 oligomerization in the ER. Here, we provide evidence that an ER-localized, 29-kDa thioredoxin-family protein (ERp29) regulates Cx43 trafficking and function. Interfering with ERp29 function destabilized monomeric Cx43 oligomerization in the ER, caused increased Cx43 accumulation in the Golgi apparatus, reduced transport of Cx43 to the plasma membrane, and inhibited gap junctional communication. ERp29 also formed a specific complex with monomeric Cx43. Together, this supports a new role for ERp29 as a chaperone that helps stabilize monomeric Cx43 to enable oligomerization to occur in the Golgi apparatus. INTRODUCTIONConnexins form gap junction channels that mediate intercellular communication by allowing the direct transfer of ions and small aqueous molecules between neighboring cells or by serving as hemichannels at the plasma membrane (Harris, 2001;Goodenough and Paul, 2003;Saez et al., 2003;Laird, 2006). There are Ͼ20 human connexin genes and one of the most ubiquitously expressed is connexin43 (Cx43). Several diseases have been linked to mutations in different connexin genes, including Cx43 (Kelsell et al., 2001;Laird, 2008). Many of these mutant connexins are not efficiently processed and lack the ability to form functional gap junction channels. Determining how mutant connexins are mistargeted requires a more complete understanding of how normal connexins are processed by the cell.A gap junction hemichannel consists of six connexins, which oligomerize before delivery to the plasma membrane (Martin and Evans, 2004;Segretain and Falk, 2004;Koval, 2006). Unlike most multimeric membrane channels, Cx43 is unusual in that it does not oligomerize in the endoplasmic reticulum (ER) (Musil and Goodenough, 1993), which is more commonly a prerequisite to further transport along the secretory pathway (Ellgaard and Helenius, 2003;Anelli and Sitia, 2008). Instead, Cx43 is transported out of the ER as an apparent monomer that then oligomerizes in the Golgi complex (Musil and Goodenough, 1993;Koval et al., 1997). Although other connexins, such as Cx46 (Koval et al., 1997), also oligomerize in the Golgi apparatus, this is not a universal pathway for connexin oligomerization because other gap junction proteins, such as Cx32, preferentially oligomerize in the ER (Martin and Evans, 2004;Koval, 2006). Understanding the molecular basis for this difference, as well as the ability of monomeric Cx43 to be transported from the ER to the Golgi apparatus has proven difficult, because little is known about chaperones that regulate connexin folding. In particular, it seemed likely that one or more chaperones would be requir...

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Section: Discussionmentioning

confidence: 88%

ERp29 Restricts Connexin43 Oligomerization in the Endoplasmic Reticulum

Das

Smith

Sarma

et al. 2009

MBoC

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“…See Schneider and Simons [24] and van der Pol et al [25] for further information on extracellularvesicle-mediated intercellular communication. pathway for electrical and metabolic signalling between cells, especially astrocytes [40][41][42]. Usually, different astrocytes are coupled through GJs to form large intercellular networks [43,44].…”

Section: (B) Gap Junctionsmentioning

confidence: 99%

Extracellular-vesicle type of volume transmission and tunnelling-nanotube type of wiring transmission add a new dimension to brain neuro-glial networks

Agnati

Fuxé

2014

Phil. Trans. R. Soc. B

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Two major types of intercellular communication are found in the central nervous system (CNS), namely wiring transmission (WT; point-to-point communication via private channels, e.g. synaptic transmission) and volume transmission (VT; communication in the extracellular fluid and in the cerebrospinal fluid). Volume and synaptic transmission become integrated because their chemical signals activate different types of interacting receptors in heteroreceptor complexes located synaptically and extrasynaptically in the plasma membrane. In VT, we focus on the role of the extracellular-vesicle type of VT, and in WT, on the potential role of the tunnelling-nanotube (TNT) type of WT. The so-called exosomes appear to be the major vesicular carrier for intercellular communication but the larger microvesicles also participate. Extracellular vesicles are released from cultured cortical neurons and different types of glial cells and modulate the signalling of the neuronal -glial networks of the CNS. This type of VT has pathological relevance, and epigenetic mechanisms may participate in the modulation of extracellular-vesicle-mediated VT. Gerdes and co-workers proposed the existence of a novel type of WT based on TNTs, which are straight transcellular channels leading to the formation in vitro of syncytial cellular networks found also in neuronal and glial cultures.

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“…Three innexinrelated proteins, called pannexins, have persisted in vertebrates, although it is not clear if they form intercellular channels (Panchin et al 2000;Bruzzone et al 2003). 7Å -resolution electron crystallographic structures of intercellular channels composed of either a carboxyterminal truncation of Cx43 (Unger et al 1999;Yeager and Harris 2007) or an M34A mutant of Cx26 (Oshima et al 2007) are available. The overall pore morphologies are similar with the exception of a "plug" in the Cx26 channel pore.…”

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confidence: 99%