Hemichannels

Little is known at present on the process of channel formation and assembly. And even less on the regulation of channel formation. A very interesting and important question is how can two cells direct their hemichannels so that they fit each other forming the intercellular pore Research in this area is still at its beginning and many of the processes involved are not well understood. But nevertheless, in this chapter the present knowledge on the regulation of channel expression and turnover will be summarized. 

Stout, C. E., Costantin, J. L., Naus, C. C., and Charles, A. C. (2002). Intercellular calcium signaling in astrocytes via ATP release through connexin hemichannels. J. Biol. Chem. 277, 10482-10488. 

Connexins are tetra-pass membrane proteins that oligomerize into hexameric hemichannels called connnexons. These gap junction proteins are encoded by a multigene family. The presence of gap junctions and the expression of connexins has been described in many areas of the developing and adult central nervous system. Up to now, only connexin (Cx) 36 and Cx45 have been found to be expressed in neurons, besides Cx43 which is expressed in the olfactory epithelium. 

Bennett MV, Contreras JE, Bukauskas FE, Saez JC (2003) New roles for astrocytes Gap junction hemichannels have something to communicate. Trends Neurosci 26 610-617. 

Contreras JE, Saez JC, Bukauskas FE, Bennett MV (2003) Gating and regulation of connexin 43 (Cx43) hemichannels. Proc Natl AcadSci USA 100 11388-11393. 

Gomez-Hernandez JM, Miguel MD, Lairosa B, Gonzalez D, Barrio L (2003) Molecular basis of calcium reguladon in connexin-32 hemichannels. Proc Natl Acad Sci USA 100 16030—16035. 

Saez JC, Contreras JE, Bukauskas FF, Retamal MA, Beimett MV (2003) Gap junction hemichannels in astrocytes of the CNS. Acta Physiol Scand 179 9-22. 

Takeuchi H, Jin S, Wang J, Zhang G, Kawanokuchi J, Kuno R, Sonobe Y, Mizuno T, Suzumura A (2006) Tumor necrosis factor-alpha induces neurotoxicity via glutamate release from hemichannels of activated microgha in an autocrine manner. J Biol Chem 281 21362-21368. 

Cx43-formed gap junctions exhibit three conductance states one of 20-30 pS, one of40-60 pS and one of70-100 pS.1,19,20 The conductance of Cx43-formed hemichannels ranges from 31 to 352 pS.21 More recently, the conductance of fully open hemichannels in HeLa-cells was found to be 220 pS however, also a sub-state of approximately 75 pS exists between the fully open and the closed state,22 suggesting that hemichannel conductance can be regulated as well. 

Cardiomyocyte death occurs during ischemia as well as during the subsequent reperfusion,69 with both necrosis and apoptosis contributing to cell death.70 Loss of cardiomyocyte volume regulation contributes to irreversible ischemic tissue injury,71 and open hemichannels might contribute to the ischemia/reperfusion-induced osmotic imbalance in cardiomyocytes.72,73... 

With a single channel conductance of more than 100 pS,1,20,22 only ten hemichannels need to be open to produce a millimolar cellular sodium influx,83 and such a millimolar increase in the intracellular sodium concentration has been measured during ischemia in whole hearts.84-86 The osmotic imbalance resulting from increased AMP, inorganic phosphate and sodium concentrations results in swelling and finally membrane rupture of the ischemic cells. 

J.E. Contreras, H.A. Sanchez, E.A. Eugenin, D. Speidel, M. Theis, K. Willecke, F.F. Bukauskas, M.V. Bennett, J.C. Saez, Metabolic inhibition induces opening of unopposed connexin 43 gap junction hemichannels and reduces gap junctional communication in cortical astrocytes in culture, Proc Natl Acad Sci USA 99,495-500 (2002). 

L.l. Plotkin, T. Bellido, Bisphosphonate-induced, hemichannel-mediated, anti-apoptosis through the Src/ ERK pathway a gap junction-independent action of conncxin43, Cell Commun Adhes 8, 377-382 (2001). 

A.P. Quist, S.K. Rhee, H. Lin, R. Lai, Physiological role of gap-junctional hemichannels. Extracellular calcium-dependent isosmotic volume regulation, Cell Biol 48, 1063-1074 (2000). 

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