Modulation of h-channels in hippocampal pyramidal neurons by p38 mitogen-activated protein kinase

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 similar to 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 similar to 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.