Inhibition of K+ outward currents by linopirdine in the cochlear outer hair cells of circling mice within the first postnatal week

Abstract

Inhibition of K+ outward currents by linopirdine in the outer hair cells (OHCs) of circling mice (homozygous (cir/cir) mice), an animal model for human deafness (DFNB6 type), was investigated using a whole cell patch clamp technique. Littermate heterozygous (+/cir) and ICR mice of the same age (postnatal day (P) 0-P6) were used as controls. Voltage steps from-100 mV to 40 mV elicited small inward currents (-100 mV∼-70 mV) and slow rising K+ outward currents (-60 mV ∼40 mV) which activated near-50 mV in all OHCs tested. Linopirdine, a known blocker of K+ currents activated at negative potentials (IK,n), did cause inhibition at varying degree (severe, moderate, mild) in K+ outward currents of heterozygous (+/cir) or homozygous (cir/cir) mice OHCs in the concentration range between 1 and 100 mM, while it was apparent only in one ICR mice OHC out of nine OHCs at 100 mM. Although the half inhibition concentrations in heterozygous (+/cir) or homozygous (cir/cir) mice OHCs were close to those reported in IK,n, biophysical and pharmacological properties of K+ outward currents, such as the activation close to-50 mV, small inward currents evoked by hyperpolarizing steps and TEA sensitivity, were not in line with IK,n reported in other tissues. Our results show that the delayed rectifier type K+ outward currents, which are not similar to IK,n with respect to biophysical and pharmacological properties, are inhibited by linopirdine in the developing (P0∼P6) homozygous (cir/cir) or heterozygous (+/cir) mice OHCs.