title: Chronic Ca2+influx through voltage-dependent Ca2+channels enhance delayed rectifier K+currents via activating Src family tyrosine kinase in rat hippocampal neurons.
abstract: Excessive influx and the subsequent rapid cytosolic elevation of Ca2+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 Ca2+level in normal as well as pathological conditions. Delayed rectifier K+channels (IDRchannels) 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 Ca2+-mediated excitotoxic conditions. In the present study, we electrophysiologically evaluated the response of IDRchannels to hyperexcitable conditions induced by high Ca2+pretreatment (3.6 mM, for 24 hours) in cultured hippocampal neurons. In results, high Ca2+-treatment significantly increased the amplitude of IDRwithout changes of gating kinetics. Nimodipine but not APV blocked Ca2+-induced IDRenhancement, confirming that the change of IDRmight be targeted by Ca2+influx through voltage-dependent Ca2+channels (VDCCs) rather than NMDA receptors (NMDARs). The VDCC-mediated IDRenhancement was not affected by either Ca2+-induced Ca2+release (CICR) or small conductance Ca2+-activated K+channels (SK channels). Furthermore, PP2 but not H89 completely abolished IDRenhancement under high Ca2+condition, indicating that the activation of Src family tyrosine kinases (SFKs) is required for Ca2+-mediated IDRenhancement. Thus, SFKs may be sensitive to excessive Ca2+influx through VDCCs and enhance IDRto activate a neuroprotective mechanism against Ca2+-mediated hyperexcitability in neurons.
authors.affiliation: Department of Physiology, School of Medicine, Jeju National University, Jeju 63243, Korea.
authors.forename: Yoon-Sil
authors.initials: YS
authors.lastname: Yang
authors.affiliation: Department of Physiology, School of Medicine, Jeju National University, Jeju 63243, Korea.
authors.forename: Sang-Chan
authors.initials: SC
authors.lastname: Jeon
authors.affiliation: Department of Physiology, College of Medicine, Konyang University, Daejeon 35365, Korea.
authors.forename: Dong-Kwan
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Physiology, School of Medicine, Jeju National University, Jeju 63243, Korea.; Institute of Medical Science, Jeju National University, Jeju 63243, Korea.
authors.forename: Su-Yong
authors.initials: SY
authors.lastname: Eun
authors.affiliation: Department of Physiology, School of Medicine, Jeju National University, Jeju 63243, Korea.; Institute of Medical Science, Jeju National University, Jeju 63243, Korea.
authors.forename: Sung-Cherl
authors.initials: SC
authors.lastname: Jung
keywords: A-type K+ channels; Delayed rectifier K+ channel; NMDA receptors; Src family tyrosine kinase; Voltage-dependent Ca2+ channel