Chronic Ca(2+) influx through voltage-dependent Ca(2+) channels enhance delayed rectifier K(+) currents via activating Src family tyrosine kinase in rat hippocampal neurons

Excessive influx and the subsequent rapid cytosolic elevation of Ca(2+) in neurons is the major cause to induce hyperexcitability and irreversible cell damage although it is an essential ion for cellular signalings. Therefore, most neurons exhibit several cellular mechanisms to homeostatically regulate cytosolic Ca(2+) level in normal as well as pathological conditions. Delayed rectifier K(+) channels (I(DR) channels) play a role to suppress membrane excitability by inducing K(+) outflow in various conditions, indicating their potential role in preventing pathogenic conditions and cell damage under Ca(2+)-mediated excitotoxic conditions. In the present study, we electrophysiologically evaluated the response of I(DR) channels to hyperexcitable conditions induced by high Ca(2+) pretreatment (3.6 mM, for 24 hours) in cultured hippocampal neurons. In results, high Ca(2+)-treatment significantly increased the amplitude of I(DR) without changes of gating kinetics. Nimodipine but not APV blocked Ca(2+)-induced I(DR) enhancement, confirming that the change of I(DR) might be targeted by Ca(2+) influx through voltage-dependent Ca(2+) channels (VDCCs) rather than NMDA receptors (NMDARs). The VDCC-mediated I(DR) enhancement was not affected by either Ca(2+)-induced Ca(2+) release (CICR) or small conductance Ca(2+)-activated K(+) channels (SK channels). Furthermore, PP2 but not H89 completely abolished I(DR) enhancement under high Ca(2+) condition, indicating that the activation of Src family tyrosine kinases (SFKs) is required for Ca(2+)-mediated I(DR) enhancement. Thus, SFKs may be sensitive to excessive Ca(2+) influx through VDCCs and enhance I(DR) to activate a neuroprotective mechanism against Ca(2+)-mediated hyperexcitability in neurons.