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Abstract
Schizophrenia is a devastating mental disorder characterized by hallucinations, delusions, cognitive and behavioural issues. Single nucleotide polymorphisms in the second intron of the KCNH2 gene, significantly associated with the diagnosis of schizophrenia, promote transcription of a truncated Kv11.1 potassium channel isoform, Kv11.1-3.1. The kinetic and pharmacological properties, and the cellular expression patterns of Kv11.1-3.1 channels in the human brain however are incompletely described.
We characterised the electrical properties of the brain specific Kv11.1-3.1 isoform compared to full length Kv11.1-1A channels. We found accelerated channel deactivation for Kv11.1-3.1, which results in significantly less current accumulation in Kv11.1-3.1 expressing cells during trains of short pulses that mimic neuronal action potentials. Furthermore, we found a significant depolarising shift in the voltage-dependence of inactivation for Kv11.1-3.1 channels compared to Kv11.1-1A channels.
Drug binding to Kv11.1 channels is affected by inactivation gating. We therefore investigated whether the altered inactivation of Kv11.1-3.1 channels affected the binding of commonly used antipsychotic drugs. Risperidone, alone among the antipsychotic drugs tested, blocked Kv11.1-3.1 channels more effectively than Kv11.1-1A channels, even under physiological conditions that mimic trains of repetitive neuronal action potential firing. We were also able to demonstrate that patients enrolled in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), homozygote for risk alleles, responded better to risperidone than to any other drug tested.
To fully understand the function of Kv11.1-3.1 channels in the brain, we need to know in which brain regions and which cell types within these regions, the channels are expressed. The dorsolateral prefrontal cortex (DLPFC) is an area of the brain that has been implicated in the pathogenesis of schizophrenia. We therefore investigated the cellular expression patterns in the DLPFC of control and schizophrenia brain samples from the NSW Tissue Resource Centre. We found that the Kv11.1-3.1 isoform is upregulated in layer III interneurons of schizophrenia patients compared to healthy controls. This result suggests that Kv11.1-3.1 channels will alter neuronal action potential shape and firing of cortical inhibitory interneurons.