Beyond the gap: functions of unpaired connexon channels

Goodenough, Daniel A.; Paul, David L.

doi:10.1038/nrm1072

Cited by 649 publications

(492 citation statements)

References 122 publications

Supporting

Mentioning

478

Contrasting

Unclassified

Order By: Relevance

“…PGE 2 in turn functions in an autocrine fashion to activate EP 2 receptor signaling, including increased intracellular cAMP and activated PKA (24). Connexins not only form gap junctions but can function as un-apposed halves of gap junction channels called hemichannels, not requiring physical contact with adjacent cells (41). Not only osteocytes but also neural progenitors and neurons, astrocytes, heart, and osteoblasts have functional hemichannels formed by Cx43.…”

Section: Wnt Signaling In Osteocytes Crosstalk With the Prostaglandimentioning

confidence: 99%

Osteocytes, mechanosensing and Wnt signaling

Bonewald¹,

Johnson²

2008

Bone

918

760

View full text Add to dashboard Cite

The majority of bone cell biology focuses on activity on the surface of the bone with little attention paid to the activity that occurs below the surface. However, with recent new discoveries, osteocytes, cells embedded within the mineralized matrix of bone, are becoming the target of intensive investigation. In this article, the distinctions between osteoblasts and their descendants, osteocytes, are reviewed. Osteoblasts are defined as cells that make bone matrix and osteocytes are thought to translate mechanical loading into biochemical signals that affect bone (re)modeling. Osteoblasts and osteocytes should have similarities as would be expected of cells of the same lineage, yet these cells also have distinct differences, particularly in their responses to mechanical loading and utilization of the various biochemical pathways to accomplish their respective functions. For example, the Wnt/ β-catenin signaling pathway is now recognized as an important regulator of bone mass and bone cell functions. This pathway is important in osteoblasts for differentiation, proliferation and the synthesis bone matrix, whereas osteocytes appear to use the Wnt/β-catenin pathway to transmit signals of mechanical loading to cells on the bone surface. New emerging evidence suggests that the Wnt/β-catenin pathway in osteocytes may be triggered by crosstalk with the prostaglandin pathway in response to loading which then leads to a decrease in expression of negative regulators of the pathway such as Sost and Dkk1. The study of osteocyte biology is becoming an intense area of research interest and this review will examine some of the recent findings that are reshaping our understanding of bone/bone cell biology. KeywordsOsteocytes; bone; Wnt/β-catenin signaling; Mechanosensation; Mechanical loading Osteocytes compose over 90-95% of all bone cells in the adult skeleton and are thought to respond to mechanical strain to send signals of resorption or formation (70). Osteocytes are usually regularly dispersed throughout the mineralized matrix especially in cortical bone. These cells are connected to each other and cells on the bone surface through dendritic processes that occupy tiny canals called canaliculi (For review see (17)). Not only do these cells communicate with each other and with cells on the bone surface but their dendritic processes are in contact with the bone marrow (59) giving them the potential to recruit osteoclast precursors to stimulate bone resorption (133)(12) and to regulate mesenchymal stem cell differentiation (48).

show abstract

Section: Wnt Signaling In Osteocytes Crosstalk With the Prostaglandimentioning

confidence: 99%

Osteocytes, mechanosensing and Wnt signaling

Bonewald¹,

Johnson²

2008

Bone

918

760

View full text Add to dashboard Cite

show abstract

“…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).…”

Section: Introductionmentioning

confidence: 99%

“…Connexins are differentially expressed in tissues with some being significantly expressed in only a few tissues and some, like Cx43, being more widespread. Gap junctions play significant regulatory roles in embryonic development, electrical coupling, apoptosis, differentiation, tissue homeostasis and metabolic transport (Goodenough & Paul, 2003;Loewenstein & Azarnia, 1988;Sohl & Willecke, 2004).…”

Section: Introductionmentioning

confidence: 99%

Key Connexin 43 Phosphorylation Events Regulate the Gap Junction Life Cycle

2007

View full text Add to dashboard Cite

Connexin43 (Cx43), the most widely expressed and abundant vertebrate gap junction protein, is phosphorylated at multiple different serine residues during its life cycle. Cx43 is phosphorylated soon after synthesis and phosphorylation changes as it traffics through the endoplasmic reticulum and Golgi to the plasma membrane ultimately forming into a gap junction structure. The electrophoretic mobility of Cx43 changes as the protein proceeds through its life cycle with prominent bands often labeled P0, P1 and P2. Many reports have indicated changes in "phosphorylation" based on these mobility shifts and others that occur in response to growth factors or other biological effectors. Here we indicate how phosphospecific and epitope specific antibodies can be utilized to show when and where certain phosphorylation events occur during the Cx43 life cycle. These reagents show that phosphorylation at S364 and or S365 is involved in forming the P1 isoform, an event that apparently regulates trafficking to or within the plasma membrane. Phosphorylation at S325, 328, and/or 330 is necessary to form a P2 isoform and this phosphorylation event is present only in gap junctions. Treatment with protein kinase C activators led to phosphorylation at S368, S279/S282 and S262 with a shift in mobility in CHO cells but not MDCK cells. The shift was dependent on MAPK activity but not phosphorylation at S279/282. However, phosphorylation at S262 could explain the shift. By defining these phosphorylation events, we have begun to be able to sort out the critical signaling pathways that regulate gap junction function.

show abstract

“…Gap junction channels are composed of proteins called connexins. Six connexin proteins form a hemichannel, or connexon, and two docked hemichannels form a gap junction channel (Goodenough & Paul, 2003). The central pore in a gap junction allows the passage of small ions and molecules up to a molecular weight around 1 kDa (Guldenagel et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Screening of gap junction antagonists on dye coupling in the rabbit retina

2007

View full text Add to dashboard Cite

Many cell types in the retina are coupled via gap junctions and so there is a pressing need for a potent and reversible gap junction antagonist. We screened a series of potential gap junction antagonists by evaluating their effects on dye coupling in the network of A-type horizontal cells. We evaluated the following compounds: meclofenamic acid (MFA), mefloquine, 2-aminoethyldiphenyl borate (2-APB), 18-α-glycyrrhetinic acid, 18-β-glycyrrhetinic acid (18-β-GA), retinoic acid, flufenamic acid, niflumic acid, and carbenoxolone. The efficacy of each drug was determined by measuring the diffusion coefficient for Neurobiotin (Mills & Massey, 1998). MFA, 18-β-GA, 2-APB and mefloquine were the most effective antagonists, completely eliminating A-type horizontal cell coupling at a concentration of 200 μM. Niflumic acid, flufenamic acid, and carbenoxolone were less potent. Additionally, carbenoxolone was difficult to wash out and also may be harmful, as the retina became opaque and swollen. MFA, 18-β-GA, 2-APB and mefloquine also blocked coupling in Btype horizontal cells and AII amacrine cells. Because these cell types express different connexins, this suggests that the antagonists were relatively non-selective across several different types of gap junction. It should be emphasized that MFA was water-soluble and its effects on dye coupling were easily reversible. In contrast, the other gap junction antagonists, except carbenoxolone, required DMSO to make stock solutions and were difficult to wash out of the preparation at the doses required to block coupling in A-type HCs. The combination of potency, water solubility and reversibility suggest that MFA may be a useful compound to manipulate gap junction coupling.

show abstract

Beyond the gap: functions of unpaired connexon channels

Cited by 649 publications

References 122 publications

Osteocytes, mechanosensing and Wnt signaling

Osteocytes, mechanosensing and Wnt signaling

Key Connexin 43 Phosphorylation Events Regulate the Gap Junction Life Cycle

Screening of gap junction antagonists on dye coupling in the rabbit retina

Contact Info

Product

Resources

About