P38 Regulates Kainic Acid-Induced Seizure and Neuronal Firing via Kv4.2 Phosphorylation

Abstract

The subthreshold, transient A-type K+ current is a vital regulator of the excitability of neurons throughout the brain. In mammalian hippocampal pyramidal neurons, this current is carried primarily by ion channels comprising Kv4.2 α-subunits. These channels occupy the somatodendritic domains of these principle excitatory neurons and thus regulate membrane voltage relevant to the input–output efficacy of these cells. Owing to their robust control of membrane excitability and ubiquitous expression in the hippocampus, their dysfunction can alter network stability in a manner that manifests in recurrent seizures. Indeed, growing evidence implicates these channels in intractable epilepsies of the temporal lobe, which underscores the importance of determining the molecular mechanisms underlying their regulation and contribution to pathologies. Here, we describe the role of p38 kinase phosphorylation of a C-terminal motif in Kv4.2 in modulating hippocampal neuronal excitability and behavioral seizure strength. Using a combination of biochemical, single-cell electrophysiology, and in vivo seizure techniques, we show that kainic acid-induced seizure induces p38-mediated phosphorylation of Thr607 in Kv4.2 in a time-dependent manner. The pharmacological and genetic disruption of this process reduces neuronal excitability and dampens seizure intensity, illuminating a cellular cascade that may be targeted for therapeutic intervention to mitigate seizure intensity and progression.

Interleukin 33-mediated inhibition of A-type K+ channels induces sensory neuronal hyperexcitability and nociceptive behaviors in mice

“…These findings are consistent with previous studies in rat ventricular myocytes showing that activation of p38 MAPK resulted in a reduction in transient outward K + currents 66 . Further observations in hippocampal pyramidal neurons showed that the increased activity of p38 markedly decreased Kv currents by phosphorylation of Kv4.2 channels 65 , 67 . In contrast, it has been demonstrated that p38 stimulates Kv currents in transfected Chinese hamster ovary cells 68 .…”

PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model

“…Inhibiting p38 MAPK also reduces the frequency of seizures, and the level of associated pathological damage within the hippocampus ( 53 ). In contrast, periods of status epilepticus activate p38 MAPK and this may mediate the subsequent anatomical changes within the cortical networks ( 54 ).…”

PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model

“…Inhibiting p38 MAPK also reduces the frequency of seizures, and the level of associated pathological damage within the hippocampus (Zhou et al, 2020). In contrast, periods of status epilepticus activate p38 MAPK, and this may mediate the subsequent anatomical changes within the cortical networks (Hu et al, 2020).…”