TY - JOUR
T1 - Neuromodulation of Na+ channel slow inactivation via cAMP-dependent protein kinase and protein kinase C
AU - Chen, Yuan
AU - Yu, Frank H.
AU - Surmeier, D. James
AU - Scheuer, Todd
AU - Catterall, William A.
N1 - Funding Information:
This work was supported by National Institutes of Health Research Grant NS15751 to W.A.C., NS34696 to D.J.S., and NIH NRSA NS43065 to Y.C. We wish to thank Joshua Held and Howard Wu for their help with the kinetic simulations and Dr. Daniel Beacham for comments on a draft of the manuscript.
PY - 2006/2/2
Y1 - 2006/2/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=31444454845&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=31444454845&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2006.01.009
DO - 10.1016/j.neuron.2006.01.009
M3 - Article
C2 - 16446144
AN - SCOPUS:31444454845
VL - 49
SP - 409
EP - 420
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 3
ER -