Neuromodulation of Na+ channel slow inactivation via cAMP-dependent protein kinase and protein kinase C.
Neurotransmitters modulate sodium channel availability through activation of G protein-coupled receptors, cAMP-dependent protein kinase (PKA), and protein kinase C (PKC). Voltage-dependent slow inactivation also controls sodium channel availability, synaptic integration, and neuronal firing. Here we show by analysis of sodium channel mutants that neuromodulation via PKA and PKC enhances intrinsic slow inactivation of sodium channels, making them unavailable for activation. Mutations in the S6 segment in domain III (N1466A,D) either enhance or block slow inactivation, implicating S6 segments in the molecular pathway for slow inactivation. Modulation of N1466A channels by PKC or PKA is increased, whereas modulation of N1466D is nearly completely blocked. These results demonstrate that neuromodulation by PKA and PKC is caused by their enhancement of intrinsic slow inactivation gating. Modulation of slow inactivation by neurotransmitters acting through G protein-coupled receptors, PKA, and PKC is a flexible mechanism of cellular plasticity controlling the firing behavior of central neurons.
Chen
Yuan
Y
Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.
Yu
Frank H
FH
Surmeier
D James
DJ
Scheuer
Todd
T
Catterall
William A
WA
D000595:Amino Acid Sequence; D001216:Asparagine / Q000235:genetics; D001224:Aspartic Acid / Q000235:genetics; D002460:Cell Line; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D004075:Diglycerides / Q000494:pharmacology; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D008954:Models, Biological; D008967:Molecular Biology / Q000379:methods; D016296:Mutagenesis / Q000502:physiology; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009712:Nucleotides, Cyclic / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D011493:Protein Kinase C / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011930:Reaction Time / Q000502:physiology / Q000528:radiation effects; D015222:Sodium Channels / Q000502:physiology*; D014162:Transfection / Q000379:methods
D004075:Diglycerides; D004791:Enzyme Inhibitors; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D009712:Nucleotides, Cyclic; C568251:SCN2A protein, human; D015222:Sodium Channels; D001224:Aspartic Acid; D001216:Asparagine; C028540:1 beta-D-ribofuranosylbenzimidazole cyclic 3',5'-phosphate; C038237:1-oleoyl-2-acetylglycerol; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C