Cell cycle- and swelling-induced activation of a Caenorhabditis elegans ClC channel is mediated by CeGLC-7alpha/beta phosphatases.
ClC voltage-gated anion channels have been identified in bacteria, yeast, plants, and animals. The biophysical and structural properties of ClCs have been studied extensively, but relatively little is known about their precise physiological functions. Furthermore, virtually nothing is known about the signaling pathways and molecular mechanisms that regulate channel activity. The nematode Caenorhabditis elegans provides significant experimental advantages for characterizing ion channel function and regulation. We have shown previously that the ClC Cl- channel homologue CLH-3 is expressed in C. elegans oocytes, and that it is activated during meiotic maturation and by cell swelling. We demonstrate here that depletion of intracellular ATP or removal of Mg2+, experimental maneuvers that inhibit kinase function, constitutively activate CLH-3. Maturation- and swelling-induced channel activation are inhibited by type 1 serine/threonine phosphatase inhibitors. RNA interference studies demonstrated that the type 1 protein phosphatases CeGLC-7alpha and beta, both of which play essential regulatory roles in mitotic and meiotic cell cycle events, mediate CLH-3 activation. We have suggested previously that CLH-3 and mammalian ClC-2 are orthologues that play important roles in heterologous cell-cell interactions, intercellular communication, and regulation of cell cycle-dependent physiological processes. Consistent with this hypothesis, we show that heterologously expressed rat ClC-2 is also activated by serine/threonine dephosphorylation, suggesting that the two channels have common regulatory mechanisms.
Rutledge
Eric
E
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Denton
Jerod
J
Strange
Kevin
K
D000255:Adenosine Triphosphate / Q000172:deficiency; D000818:Animals; D000090007:CLC-2 Chloride Channels; D017173:Caenorhabditis elegans / Q000166:cytology / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000502:physiology; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005656:Fungal Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D015347:RNA Probes; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015032:Zinc / Q000494:pharmacology
D000090007:CLC-2 Chloride Channels; D029742:Caenorhabditis elegans Proteins; D018118:Chloride Channels; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D015347:RNA Probes; C417201:clh-3 protein, C elegans; D000255:Adenosine Triphosphate; D010770:Phosphotransferases; D017346:Protein Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; D015032:Zinc