Blockade of Kv3.1 by MK-801, a PCP-Derivative NMDA Receptor Inhibitor: Implications for Models of Schizophrenia

MK-801, a phencyclidine (PCP) derivative also known as dizocilpine, is a potent noncompetitive antagonist of the N-Methyl-D-aspartate receptor (NMDAr). The NMDAr plays a critical role in mediating excitatory synaptic transmission in the central nervous system (CNS) and is important in regulating synaptic plasticity, learning, and memory. MK-801 is known to induce schizophrenia-like phenotypes in animal models by blocking the NMDAr. Several studies have reported that the cognitive impairment associated with schizophrenia is linked to functional defects of ion channels in parvalbumin-positive GABAergic interneurons. Kv3.1 is a voltage-gated K+ (Kv) channel involved in the rapid repolarization of the action potential in neurons; it is richly expressed in parvalbumin-positive GABAergic interneurons and is associated with fast, repetitive spike generation. A decrease of Kv3.1 in the CNS has been reported to be associated with schizophrenia. In the present study, the effect of MK-801 on Kv3.1 was investigated using the whole-cell patch-clamp technique in Chinese hamster ovary (CHO) cells stably expressing Kv3.1. MK-801 caused a concentration-dependent inhibition of Kv3.1, with an IC50 of 10.81 M and a Hill coefficient of 0.89. The blocking potency was stronger at depolarized potentials, indicating a voltage-dependent block. MK-801 also produced a use-dependent block, inducing progressive inhibition with repeated stimulation at increased frequencies (1 Hz and 2 Hz), consistent with a delay in recovery from inactivation of Kv3.1 in the presence of MK-801. In addition, MK-801 induced a hyperpolarizing shift in the voltage dependence of the steady-state inactivation curve of Kv3.1. Taken together, these results indicate that MK-801 blocks Kv3.1 expressed in CHO cells in a concentration-, voltage-, and state-dependent manner. Given the importance of Kv3.1 in parvalbumin-positive, fast-spiking GABAergic interneurons, these findings suggest that MK-801 may alter the firing patterns of these inhibitory neurons, contributing to the onset and symptoms of schizophrenia.

Park, T. J., PARK, S. W., Park, S., Lim, Y., Lee, H., Kim, J., Kim, H., Kim, D. H., O-Uchi, J., Seo, M. S., An, J. R., Choi, B. H., Bae, Y. M.

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