| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Albert Eintein College of Medicine
2 Albert Einstein College of Medicine
3 Oswaldo Cruz
4 University of Miami Medical School
* To whom correspondence should be addressed. E-mail: scemes{at}aecom.yu.edu.
Pannexin1 (Panx1), an ortholog to invertebrate innexin gap junctions, has recently been proposed to be the pore induced by P2X7 receptor activation. We explored the pharmacological action of compounds known to block gap junctions on Panx1 channels activated by the P2X7R and the mechanisms involved in the interaction between these two proteins. Whole cell recordings revealed distinct P2X7R and Panx1 currents in response to agonists. Activation of Panx1 currents following P2X7R stimulation or by membrane depolarization was blocked by Panx1 siRNA as well as with mefloquine > carbenoxolone > flufenamic acid. Incubation of cells with KN-62, a P2X7R antagonist, prevented current activation by BzATP. Membrane permeabilization to dye induced by BzATP was also prevented by Panx1 siRNA and by carbenoxolone and mefloquine. Membrane permeant (TAT-P2X7) peptides, provided evidence that the SH3-death domain of the C-terminus of the P2X7R is involved in the initial steps of the signal transduction events leading to Panx1 activation and that a Src tyrosine kinase is likely involved in this process. Competition assays indicated that 20 µM TAT-P2X7 peptide caused 50% reduction in Src binding to the P2X7R complex. Src tyrosine phosphorylation following BzATP stimulation was reduced by KN-62, TAT-P2X7 peptide and by the Src tyrosine inhibitor PP2, and that these compounds prevented both large conductance Panx1 currents and membrane permeabilization. These results together with the lack Panx1 tyrosine phosphorylation in response to P2X7R stimulation indicate the involvement of an additional molecule in the tyrosine kinase signal transduction pathway mediating Panx1 activation through the P2X7 receptor.
This article has been cited by other articles:
|
|
 |
|
  W. R. Silverman, J. P. de Rivero Vaccari, S. Locovei, F. Qiu, S. K. Carlsson, E. Scemes, R. W. Keane, and G. Dahl The Pannexin 1 Channel Activates the Inflammasome in Neurons and Astrocytes J. Biol. Chem., July 3, 2009; 284(27): 18143 - 18151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Iglesias, G. Dahl, F. Qiu, D. C. Spray, and E. Scemes Pannexin 1: The Molecular Substrate of Astrocyte "Hemichannels" J. Neurosci., May 27, 2009; 29(21): 7092 - 7097. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Monif, C. A. Reid, K. L. Powell, M. L. Smart, and D. A. Williams The P2X7 Receptor Drives Microglial Activation and Proliferation: A Trophic Role for P2X7R Pore J. Neurosci., March 25, 2009; 29(12): 3781 - 3791. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Skals, N. R. Jorgensen, J. Leipziger, and H. A. Praetorius {alpha}-Hemolysin from Escherichia coli uses endogenous amplification through P2X receptor activation to induce hemolysis PNAS, March 10, 2009; 106(10): 4030 - 4035. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Ma, H. Hui, P. Pelegrin, and A. Surprenant Pharmacological Characterization of Pannexin-1 Currents Expressed in Mammalian Cells J. Pharmacol. Exp. Ther., February 1, 2009; 328(2): 409 - 418. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Qiu and G. Dahl A permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP Am J Physiol Cell Physiol, February 1, 2009; 296(2): C250 - C255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. R. Dubyak Both sides now: multiple interactions of ATP with pannexin-1 hemichannels. Focus on "A permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP" Am J Physiol Cell Physiol, February 1, 2009; 296(2): C235 - C241. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
