The Impact Of Copper On Rat Hippocampal Cal Neurons In The A-current And Delayed Rectifier Potassium Current

Copper (Cu²⁺) is an essential transition metal that plays a critical role in the central nervous system (CNS). However, aberrant copper homeostasis is harmful to CNS and excess copper is extremely toxic in the CNS. Pathologically increased accumulation of copper in central neurons induce severe neurological disorders, such as neurological degeneration, mental retardation, which has been postulated to play a role in the pathogenesis of Wilson's disease (WD) and Alzheimer's disease (AD). Recently, many human neurological disease pathgenesis has been shown to be related to abnormalities of voltage-gated K⁺ channel function, such as learning and memory impairing, ataxia, epilepsy and deafness. Recent evidence demonstrated that voltage-dependent transient outward and delayed rectifier K⁺ channel function have been implicated in learning and memory. In addition, high concentrations of Cu²⁺ has been measured in the brain for patients with WD or AD. Thus, in this study, we investigated in detail the effects of physiologically and pathologically relevant copper on I_a and I_k by using the whole-cell patch-clamp technique in the acutely dissociated rat hippocampal CA1 pyramid neurons. The main results were summarized as following:1. Effects of copper on A-type potassium currents (I_A) in acutely dissociated rathippocampal CA1 neuronsExtracellular application of various concentrations of Cu²⁺(1-1000 μM) reversibly reduced the amplitude of I_a in a dose-dependent manner with an IC₅₀ value of 130 μM. 100 and 300 μM Cu²⁺significantly shifted the V_1/2 of steady-state activation curve to the depolarizing direction by 7.2 and 17.2 mV, respectively, indicating that Cu²⁺ decreased the activation of I_a. For state-inactivation curves, 100 and 300 μM Cu²⁺ markedly shifted the V_1/2 to the depolarizing direction by 5.2 and 9.0 mV, respectively, indicating that channels were less likely to be inactivated at higher concentrations of Cu²⁺ at any given potential. In addition, higher concentrations Cu²⁺ markedly increased the decay at a prepulse potential of -110 mV and significantly slowed the recovery of I_k from inactivation. These results suggest it is possible for...