196,141 research outputs found
EA-1 mutations alter the fast inactivation properties of Kv1.1 channels conferred by Kv1.4 and Kvbeta1.1 subunits
No full textEpisodic ataxia type-1 mutations alter the open state stability of voltage-gated K+ channels and the cell resting potential.
No full textEpisodic Ataxia Type 1 Mutation F184C Alters Zn2+-Induced Modulation of the Human K+ Channel Kv1.4-Kv1.1/Kvb1.1
No full textEpisodic ataxia type 1 (EA1) is a Shaker-like channelopathy characterized by continuous myokymia and attacks of imbalance with jerking movements of the head, arms, and legs. Although altered expression and gating properties of Kv1.1 channels underlie EA1, several disease-causing mechanisms remain poorly understood. It is likely that Kv1.1, Kv1.4, and Kv1.1 subunits form heteromeric channels at hippocampal mossy fiber boutons from which Zn2+ ions are released into the synaptic cleft in a Ca2+- dependent fashion. The sensitivity of this macromolecular channel complex to Zn2+ is unknown. Here, we show that this heteromeric channel possesses a high-affinity (<10 M) and a low-affinity (<0.5 mM) site for Zn2+, which are likely to regulate channel availability at distinct presynaptic membranes. Furthermore, the EA1 mutation F184C, located within the S1 segment of the Kv1.1 subunit, markedly decreased the equilibrium dissociation constants for Zn2+ binding to the high- and low-affinity sites. The functional characterization of the Zn2+ effects on heteromeric channels harboring the F184C mutation also showed that this ion significantly 1) slowed the activation rate of the channel, 2) increased the time to reach peak current amplitude, 3) decreased the rate and amount of current undergoing N-type inactivation, and 4) slowed the repriming of the channel compared with wild-type channels. These results demonstrate that the EA1 mutation F184C will not only sensitize the homomeric Kv1.1 channel to extracellular Zn2+, but it will also endow heteromeric channels with a higher sensitivity to this metal ion. During the vesicular release of Zn2+, its effects will be in addition to the intrinsic gating defects caused by the mutation, which is likely to exacerbate the symptoms by impairing the integration and transmission of signals within specific brain areas
The Episodic Ataxia Type 1 Mutation F184C Alters the Zn2+ Modulation of the Human Kv1.4-Kv1.1/Kvbeta1 Channel
No full textEA-1 mutations alter the fast inactivation properties of Kv1.1 channels conferred by Kv1.4 and Kvbeta1.1 subunits
No full textRole of the S1 segment in the voltage-dependent gating of Kv1.1 channels revealed by naturally occurring pathogenic mutations
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Role of receptor protein tyrosine phosphatase alpha (RPTPalpha) and tyrosine phosphorylation in the serotonergic inhibition of voltage-dependent potassium channels.
No full textThe activity of voltage-gated potassium (Kv) channels can be dynamically modulated by several events, including neurotransmitter-stimulated biochemical cascades mediated by G-protein-coupled receptors. By using a heterologous expression system, we show that activating the 5-HT2C receptor inhibits both Kv1.1 and Kv1.2 channels through a tyrosine phosphorylation mechanism. The major molecular determinants of channel inhibition were identified as two tyrosine residues located in the N-terminal region of the Kv channel subunit. Furthermore, we demonstrate that receptor protein tyrosine phosphatase alpha (RPTPalpha), a receptor protein tyrosine phosphatase, co-ordinates the inhibition process mediated via 5-HT2C receptors. We therefore propose that the serotonergic regulation of human Kv1.1 and Kv1.2 channel activity by the 5-HT2C receptor involves the dual coordination of both RPTPalpha and specific tyrosine kinases coupled to this receptor
Human voltage-dependent potassium channel heteropolymerization results in episodic ataxia type-1 myokymia syndrome.
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