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 ϳ25 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 ϳ11 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.
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