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The Journal of Neuroscience, July 26, 2006, 26(30):7995-8003; doi:10.1523/JNEUROSCI.2069-06.2006

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Cellular/Molecular
Modulation of h-Channels in Hippocampal Pyramidal Neurons by p38 Mitogen-Activated Protein Kinase

Nicholas P. Poolos,^1,3 James B. Bullis,² and Miranda K. Roth³

¹Department of Neurology and Regional Epilepsy Center, ²Neurobiology and Behavior Program, and ³Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98104

Correspondence should be addressed to Nicholas P. Poolos, University of Washington, 325 9th Avenue, Box 359745, Seattle, WA 98104. npoolos{at}u.washington.edu

Hyperpolarization-activated cyclic nucleotide-gated ion channels (h-channels; I_h; HCN) modulate intrinsic excitability in hippocampal and neocortical pyramidal neurons, among others. Whereas I_h mediated by the HCN2 isoform is regulated by cAMP, there is little known about kinase modulation of I_h, especially for the HCN1 isoform predominant in pyramidal neurons. We used a computational method to identify a novel kinase modulator of h-channels, p38 mitogen-activated protein kinase (p38 MAPK). Inhibition of p38 MAPK in hippocampal pyramidal neurons caused a 25 mV hyperpolarization of I_h voltage-dependent activation. This downregulation of I_h produced hyperpolarization of resting potential, along with increased input resistance and temporal summation of excitatory inputs. Activation of p38 MAPK caused a 11 mV depolarizing shift in I_h activation, along with depolarized resting potential, and decreased input resistance and temporal summation. Inhibition of related MAPKs, ERK1/2 (extracellular signal-related kinase 1/2) and JNK (c-Jun N-terminal kinase), produced no effect on I_h. These results show that p38 MAPK is a strong modulator of h-channel biophysical properties and may deserve additional exploration as a link between altered I_h and pathological conditions such as epilepsy.

Key words: HCN; I_h; kinase; dendrite; PLP; hippocampus; epilepsy

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Received Sept. 20, 2005; revised June 22, 2006; accepted June 23, 2006.

Correspondence should be addressed to Nicholas P. Poolos, University of Washington, 325 9th Avenue, Box 359745, Seattle, WA 98104. npoolos{at}u.washington.edu

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