Chronic Ca²⁺ influx through voltage-dependent Ca²⁺ channels enhance delayed rectifier K⁺ currents via activating Src family tyrosine kinase in rat hippocampal neurons.
10.4196/kjpp.2017.21.2.259
- Author:
Yoon Sil YANG
1
;
Sang Chan JEON
;
Dong Kwan KIM
;
Su Yong EUN
;
Sung Cherl JUNG
Author Information
1. Department of Physiology, School of Medicine, Jeju National University, Jeju 63243, Korea. jungsc@jejunu.ac.kr
- Publication Type:Original Article
- Keywords:
A-type K+ channels;
Delayed rectifier K⁺ channel;
NMDA receptors;
Src family tyrosine kinase;
Voltage-dependent Ca²⁺ channel
- MeSH:
Animals;
Calcium Channels;
Cytosol;
Humans;
Kinetics;
Membranes;
Neurons*;
Nimodipine;
Protein-Tyrosine Kinases*;
Rats*;
Receptors, N-Methyl-D-Aspartate;
src-Family Kinases;
Tyrosine*
- From:The Korean Journal of Physiology and Pharmacology
2017;21(2):259-265
- CountryRepublic of Korea
- Language:English
-
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 (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 Ca²⁺-mediated excitotoxic conditions. In the present study, we electrophysiologically evaluated the response of IDR channels 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 IDR without changes of gating kinetics. Nimodipine but not APV blocked Ca²⁺-induced IDR enhancement, confirming that the change of I(DR) might be targeted by Ca²⁺ influx through voltage-dependent Ca²⁺ channels (VDCCs) rather than NMDA receptors (NMDARs). The VDCC-mediated I(DR) enhancement 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 I(DR) enhancement under high Ca²⁺ condition, indicating that the activation of Src family tyrosine kinases (SFKs) is required for Ca²⁺-mediated I(DR) enhancement. Thus, SFKs may be sensitive to excessive Ca²⁺ influx through VDCCs and enhance I(DR) to activate a neuroprotective mechanism against Ca²⁺-mediated hyperexcitability in neurons.
