mGlu4 potentiation of K(2P)2.1 is dependant on C-terminal dephosphorylation.
Two-pore domain potassium (K(2P)) channels are proposed to underlie the background or leak current found in many excitable cells. Extensive studies have been performed investigating the inhibition of K(2P)2.1 by Galpha(q)- and Galpha(s)-coupled G-protein-coupled receptors (GPCRs), whereas in the present study we investigate the mechanisms underlying Galpha(i)/Galpha(o)-coupled GPCR increases in K(2P)2.1 activity. Activation of mGlu4 increases K(2P)2.1 activity, with pharmacological inhibition of protein kinases and phosphatases revealing the involvement of PKA whereas PKC, PKG or protein phosphatases play no role. Mutational analysis of potential C-terminal phosphorylation sites indicates S333 to control approximately 70%, with S300 controlling approximately 30% of the increase in K(2P)2.1 activity following mGlu4 activation. These data reveal that activation of mGlu4 leads to an increase in K(2P)2.1 activity through a reduction in C-terminal phosphorylation, which represents a novel mechanism by which group III mGlu receptors may regulate cell excitability and synaptic activity.
Cain
Stuart M
SM
Strathclyde Institute of Pharmacy and Biomedical Sciences, The University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK.
Meadows
Helen J
HJ
Dunlop
John
J
Bushell
Trevor J
TJ
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009154:Mutation / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation; D011422:Propionates / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D051669:Shab Potassium Channels / Q000235:genetics / Q000502:physiology*; D014162:Transfection
C114785:2-amino-4-phosphono-propinate; D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; D010446:Peptide Fragments; D011422:Propionates; D018094:Receptors, Metabotropic Glutamate; D051669:Shab Potassium Channels; D049452:Green Fluorescent Proteins; D015124:8-Bromo Cyclic Adenosine Monophosphate; D000242:Cyclic AMP; D037342:Pertussis Toxin; C108823:metabotropic glutamate receptor 4