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The manuscript by Huffaker et al. extends the growing number of cardiac potassium channels that have found their way into the brain and onto the list of putative therapeutic targets for the treatment of neurological and psychiatric disease. In an extensive series of experiments, these investigators demonstrate an association between single nucleotide polymorphisms in a gene encoding an inwardly rectifying potassium channel (KCNH2), the expression of a previously unknown isoform (KCNH2-3.1), and schizophrenia. Named for the dance exhibited by ether-intoxicated fruit fly mutants in which the gene family was first identified, ether-a-go-go related gene or ERG K+ channels contribute to the repolarization of cardiac action potentials and the propensity of antipsychotic drugs to prolong the QT interval, a direct result of their ability to attenuate this current in the heart. The unique gating properties of ERG K+ channels (for review, see Shepard et al., 2007) give rise to a strong resurgent current that can profoundly alter both intermediate and slow components of neuronal signaling. Thus, ERG currents have been shown to alter spike timing (e.g., latency to first spike in a stimulus-evoked train, spike frequency adaptation) in cerebellar Purkinje (Sacco et al., 2003), medial vestibular nucleus (Pessia et al., 2008), and cultured cortical neurons, while in dopamine cells, they appear to underlie a slow afterhyperpolarization envisioned to contribute to the termination of plateau oscillations and the obligatory pause in firing after a burst of spikes (Canavier et al., 2007; Nedergaard, 2004).

Identification of a primate-specific KCNH2-3.1 isoform in hippocampus and cortex whose expression in brain alters the function of the channel begs a number of questions that will undoubtedly be the focus of subsequent research. Foremost among these is whether the therapeutic effects of antipsychotic drugs derive in some measure from their ability to block ERG channels containing the KCNH2-3.1 protein. Although the truncated KCNH2-3.1 isoform is unique to primates, phenotypic changes associated with expression of the protein result from loss of the PAS domain, a region of the protein responsible for the resurgent nature of the outward current. In addition to increasing the rate of ERG channel deactivation, expression of the truncated isoform may reduce the number of functional channels brought to the surface as suggested by the reported reduction in ERG current density in rat cortical neurons transfected with human KCNH2-3.1. The functional consequences associated with the loss of the PAS domain in individual cells can be characterized using dynamic clamp—a technique in which a computer simulation is used to introduce an artificial membrane conductance into individual neurons. However, the effects of the mutation on channel trafficking and assessment of the myriad of conductance states likely to result from heterologous expression with other ERG channel subunits will require a transgenic model, which if history serves, the Weinberger group has already begun constructing.

References:

Canavier CC, Oprisan SA, Callaway JC, Ji H, Shepard PD. Computational model predicts a role for ERG current in repolarizing plateau potentials in dopamine neurons: implications for modulation of neuronal activity. J Neurophysiol . 2007 Nov 1 ; 98(5):3006-22. Abstract

Nedergaard S. A Ca2+-independent slow afterhyperpolarization in substantia nigra compacta neurons. Neuroscience . 2004 Jan 1 ; 125(4):841-52. Abstract

Pessia M, Servettini I, Panichi R, Guasti L, Grassi S, Arcangeli A, Wanke E, Pettorossi VE. ERG voltage-gated K+ channels regulate excitability and discharge dynamics of the medial vestibular nucleus neurones. J Physiol . 2008 Oct 15 ; 586(Pt 20):4877-90. Abstract

Sacco T, Bruno A, Wanke E, Tempia F. Functional roles of an ERG current isolated in cerebellar Purkinje neurons. J Neurophysiol . 2003 Sep 1 ; 90(3):1817-28. Abstract

Shepard PD, Canavier CC, Levitan ES. Ether-a-go-go-related gene potassium channels: what's all the buzz about? Schizophr Bull . 2007 Nov 1 ; 33(6):1263-9. Abstract

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