A Novel Role for HERG K⁺ Channels: Spike‐Frequency Adaptation

Abstract

1. The regular firing of a Hodgkin-Huxley neurone endowed with fast Na¤ and delayed K¤ channels can be converted into adapting firing by appending HERG (human eag-related gene) channels. 2. The computer model predictions were verified by studying the firing properties of F-11 DRG neurone ² neuroblastoma hybrid cells induced to differentiate by long-term exposure to retinoic acid. These cells, which express HERG currents (IHERG), show clear spike-frequency adaptation of their firing when current clamped with long depolarizations. 3. In agreement with the prediction, the selective blocking of IHERG by class III antiarrhythmic drugs always led to the disappearance of the spike-frequency adaptation, and the conversion of adapting firing to regular firing. 4. It is proposed that, in addition to their role in the repolarization of the heart action potential, HERG channels may sustain a process of spike-frequency adaptation, and hence contribute to the control of burst duration in a way that is similar to that of the K¤ currents, IAHP, IC and IM. In addition to the known cardiac arrhythmia syndrome (LQT2), genetic mutations or an altered HERG expression could lead to continuous hyperexcitable states sustained by the inability of nerve or endocrine cells to accommodate to repetitive stimuli. This might help in clarifying the pathogenesis of still undefined idiopathic familial epilepsies.

Characterization of Inhibition by Risperidone of the Inwardly Rectifying K+ Current in Pituitary GH3 Cells

“…These findings are consistent with an earlier work showing that in neuroblastoma cells, the erg-mediated K ϩ current is responsible for the adaptation of spike frequency (Chiesa et al 1997). However, it still needs to be further clarified whether the block of I K(IR) by risperidone is voltagedependent, because it appears to be difficult to compare the kinetics of currents consisting predominantly of a transient inward component (i.e., I K(IR) ) in the control with those of currents primarily due to a sustained component in the presence of risperidone.…”

“…In addition, because single GH 3 cells have a very high input resistance (1-5 GΩ), only small amounts of current are sufficient to cause the change in membrane polarization. Therefore, a block of outflow through this type of ionic channels would result in a depolarization and affect the firing rate of these cells (Chiesa et al 1997).…”

Multiple Interactions between Cytoplasmic Domains Regulate Slow Deactivation of Kv11.1 Channels

“…Members of the KCNH family share relatively close sequence homology but differ in the voltage dependence and kinetics of channel gating. The resulting diversity in current phenotype allows KCNH family members to perform a diverse range of physiological roles in the heart, during neuronal action potential firing (2), during phasic contraction in a range of smooth muscles (3,4), in hormone secretion (5)(6)(7), and in cell proliferation (8).…”

“…KCNH family members also have large N and C termini that can have profound effects on channel function. For example, the N-Cap/Per-Arnt-Sim (PAS) 2 domain on the N termini plays a critical role in slowing deactivation gating in Kv11.1 channels (12)(13)(14)(15)(16), and this is likely mediated by an interaction with the cyclic nucleotide binding homology (cNBH) domain in the C terminus (17). A crystal structure complex of the PAS and cNBH domains from a closely related murine Kv10.1 channel provides the first atomic detail that these domains form a direct interaction (18).…”

Neoglucosylated Collagen Matrices Drive Neuronal Cells to Differentiate

“…This observation shows for the first time that F11 cells can be driven from proliferation to differentiation without the use of chemical differentiating agents. 20,21 Glycosylated proteins of the extracellular matrix are specifically recognized by cell surface proteins which are lectins or which contain characteristic lectin-domains. 22 Lectin-like proteins have been identified on the surface of a neuroblastoma cell line, associated with many proteins in high molecular weight complexes, and one of them, calreticulin, was found to be essential for adhesion and neurite formation.…”