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

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Abstract
Hyperpolarization-activated cyclic nucleotide-gated ion channels (h-channels;Ih; HCN) modulate intrinsic excitability in hippocampal and neocortical pyramidal neurons, among others. WhereasIhmediated by the HCN2 isoform is regulated by cAMP, there is little known about kinase modulation ofIh, 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 ofIhvoltage-dependent activation. This downregulation ofIhproduced 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 inIhactivation, 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 onIh. These results show that p38 MAPK is a strong modulator of h-channel biophysical properties and may deserve additional exploration as a link between alteredIhand pathological conditions such as epilepsy.