Dysregulation of hyperpolarization-activated
cyclic nucleotide-gated
cation (HCN) channels alters neuronal excitability. However, the role of HCN channels in
status epilepticus is not fully understood. In this study, we established rat models of
pentylenetetrazole-induced
status epilepticus. We performed western blot assays and immunofluorescence staining. Our results showed that
HCN1 channel protein expression, particularly HCN1
surface protein, was significantly decreased in the hippocampal CA1 region, whereas the expression of
HCN2 channel protein was unchanged. Moreover, metabolic
glutamate receptor 1 (
mGluR1)
protein expression was increased after
status epilepticus. The
mGluR1 agonist (RS)-3,5-dihydroxyphenylglycine injected intracerebroventricularly increased the sensitivity and severity of
pentylenetetrazole-induced
status epilepticus, whereas application of the
mGluR1 antagonist (+)-2-methyl-4-
carboxyphenylglycine (
LY367385) alleviated the severity of
pentylenetetrazole-induced
status epilepticus. The results from double immunofluorescence labeling revealed that
mGluR1 and HCN1 were co-localized in the CA1 region. Subsequently, a
protein kinase A inhibitor (H89) administered intraperitoneally successfully reversed
HCN1 channel inhibition, thereby suppressing the severity and prolonging the latency of
pentylenetetrazole-induced
status epilepticus. Furthermore,
H89 reduced the level of
mGluR1, downregulated cyclic
adenosine monophosphate (
cAMP)/protein kinase A expression, significantly increased tetratricopeptide repeat-containing Rab8b-interacting
protein (TRIP8b) (1a-4) expression, and restored TRIP8b (1b-2) levels. TRIP8b (1a-4) and TRIP8b (1b-2) are subunits of Rab8b interacting
protein that regulate HCN1
surface protein.