MPS-1 is a K+ channel β-subunit and a serine/threonine kinase

Cai, Shi; Hernandez, Leonardo; Wang, Yi; Park, Ki Ho; Sesti, Federico

doi:10.1038/nn1557

Cited by 31 publications

(34 citation statements)

References 42 publications

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“…Adams and Dudek, 2005) in conjunction with a relatively fast turnover rate of the channels involved. Alternatively, ion channels can also express enzymatic activity, which could regulate inter-ion channel activation directly (Runnels et al, 2001;Cai et al, 2005). The existence of multi-molecular complexes, including ion channels, enzymes, and cofactors capable of recruiting and activating enzymes (Catterall et al, 2006;Levitan, 2006), may provide the molecular framework for the coordinated regulation of multiple channels.…”

Section: Discussionmentioning

confidence: 99%

Neuromodulators, Not Activity, Control Coordinated Expression of Ionic Currents

Khorkova¹,

Golowasch²

2007

J. Neurosci.

138

200

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Electrical activity in identical neurons across individuals is often remarkably similar and stable over long periods. However, the ionic currents that determine the electrical activity of these neurons show wide animal-to-animal amplitude variability. This seemingly random variability of individual current amplitudes may obscure mechanisms that globally reduce variability and that contribute to the generation of similar neuronal output. One such mechanism could be the coordinated regulation of ionic current expression. Studying identified neurons of the Cancer borealis pyloric network, we discovered that the removal of neuromodulatory input to this network (decentralization) was accompanied by the loss of the coordinated regulation of ionic current levels. Additionally, decentralization induced large changes in the levels of several ionic currents. The loss of coregulation and the changes in current levels were prevented by continuous exogenous application of proctolin, an endogenous neuromodulatory peptide, to the pyloric network. This peptide does not exert fast regulatory actions on any of the currents affected by decentralization. We conclude that neuromodulatory inputs to the pyloric network have a novel role in the regulation of ionic current expression. They can control, over the long term, the coordinated expression of multiple voltage-gated ionic currents that they do not acutely modulate. Our results suggest that current coregulation places constraints on neuronal intrinsic plasticity and the ability of a network to respond to perturbations. The loss of conductance coregulation may be a mechanism to facilitate the recovery of function.

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Section: Discussionmentioning

confidence: 99%

Neuromodulators, Not Activity, Control Coordinated Expression of Ionic Currents

Khorkova¹,

Golowasch²

2007

J. Neurosci.

138

200

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“…Averages were computed from groups of 10 -15 cells. tissue, KVS-1 forms a complex with MPS-1, a bifunctional ␤-subunit that possesses kinase activity (29). When MPS-1 is co-expressed with KVS-1 in CHO cells, it accelerates the rate of inactivation through mechanisms that are independent of its enzymatic activity.…”

Section: Discussionmentioning

confidence: 99%

A New Mode of Regulation of N-type Inactivation in a Caenorhabditis elegans Voltage-gated Potassium Channel

Cai¹,

Sesti²

2007

Journal of Biological Chemistry

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N-type inactivation in voltage-gated K؉ (Kv) channels is a widespread means to modulate neuronal excitability and signaling. Here we have shown a novel mechanism of N-type inactivation in a Caenorhabditis elegans Kv channel. The N-terminal sequence of KVS-1 contains a domain of 22 amino acids that resembles the inactivation ball in A-type channels, which is preceded by a domain of eighteen amino acids. Wild type KVS-1 currents can be described as A-type; however, their kinetics are significantly (ϳ5-fold) slower. When the putative inactivation ball is deleted, the current becomes non-inactivating. Inactivation is restored in non-inactivating channels by diffusion of the missing inactivation domain in the cytoplasm. Deletion of the domain in front of the ball speeds inactivation kinetics ϳ5-fold. We conclude that KVS-1 is the first example of a novel type of Kv channel simultaneously possessing an N-inactivating ball preceded by an N inactivation regulatory domain (NIRD) that acts to slow down inactivation through steric mechanisms.A-type channels constitute an important group of voltagegated K ϩ (Kv) 2 channels that play a prominent role in the control of neuronal and muscular excitability, synaptic input, and neurotransmitter release (1-4). The name "A-type" stems from the typical profile of these currents, rapid activation at subthreshold voltages followed by fast inactivation (4). In many neurons, A-type channels are usually silent at resting membrane potentials. They, however, transiently activate during the decay of the after-hyperpolarization phase of the action potential, delaying depolarization (5). Thus, A-type inactivation is a key physiological feature that allows control of the neuronal firing frequency by regulating the interval between consecutive action potentials (4). In the late 70s, Armstrong and Bezanilla (6), in an effort to explain the mechanism of A-type inactivation, proposed the "ball-and-chain" model, which postulates that a positively charged inactivation particle (the ␣-ball) on a tether prevents the movement of ions by physically occluding the pore. Using the Drosophila channel Shaker, Hoshi, Zagotta, and Aldrich (7, 8) identified the location and molecular composition of the ball. This is composed of the first Ϯ20 amino acids in the N terminus (thus the name "N-type" inactivation) followed by 40 or more residues constituting the chain. The inactivation ball possesses two essential chemical characteristics (Fig. 1): the first half is composed of hydrophobic residues, and the rest has a net positive charge that pushes the ball toward its channel receptor site upon depolarization (9, 10). Because of the dynamic nature of N-type inactivation, the details of the mechanisms have been unknown for a long time. Recently, using crystallography, Mackinnon and colleagues (11, 12) have proposed that N inactivation occurs as a sequential reaction; the ball initially binds to the T1 domain surface by electrostatic interactions, and then it enters through the lateral portals that connect the cytopla...

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“…Incorporation of accessory β-subunits modifies the function of K V channels to suit the diverse requirements of different tissues. KCNE genes encode minK-related peptides (MiRPs) (4-6), β-subunits with a single transmembrane span that assemble with a wide array of K V α-subunits (7,8) to control surface expression, voltage dependence, and kinetics of gating transitions, unitary conductance, ion selectivity, and pharmacology of the resultant channel complexes (4,(9)(10)(11)(12)(13)(14)(15). I Kslow (I Ks ) channels in the heart and inner ear are formed by the α-subunit encoded by KCNQ1 (called Q1, K V LQT1, K V 7.1, or KCNQ1) and the β-subunit encoded by KCNE1 (called E1, mink, or KCNE1) (16,17).…”

mentioning

confidence: 99%

Individual I _Ks channels at the surface of mammalian cells contain two KCNE1 accessory subunits

Plant

Xiong

Dai

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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KCNE1 (E1) β-subunits assemble with KCNQ1 (Q1) voltage-gated K + channel α-subunits to form I Kslow (I Ks ) channels in the heart and ear. The number of E1 subunits in I Ks channels has been an issue of ongoing debate. Here, we use single-molecule spectroscopy to demonstrate that surface I Ks channels with human subunits contain two E1 and four Q1 subunits. This stoichiometry does not vary. Thus, I Ks channels in cells with elevated levels of E1 carry no more than two E1 subunits. Cells with low levels of E1 produce I Ks channels with two E1 subunits and Q1 channels with no E1 subunits-channels with one E1 do not appear to form or are restricted from surface expression. The plethora of models of cardiac function, transgenic animals, and drug screens based on variable E1 stoichiometry do not reflect physiology.V oltage-gated potassium (K V ) channels include four α-subunits that form a single, central ion conduction pathway with four peripheral voltage sensors (1-3). Incorporation of accessory β-subunits modifies the function of K V channels to suit the diverse requirements of different tissues. KCNE genes encode minK-related peptides (MiRPs) (4-6), β-subunits with a single transmembrane span that assemble with a wide array of K V α-subunits (7, 8) to control surface expression, voltage dependence, and kinetics of gating transitions, unitary conductance, ion selectivity, and pharmacology of the resultant channel complexes (4, 9-15). I Kslow (I Ks ) channels in the heart and inner ear are formed by the α-subunit encoded by KCNQ1 (called Q1, K V LQT1, K V 7.1, or KCNQ1) and the β-subunit encoded by KCNE1 (called E1, mink, or KCNE1) (16,17). Inherited mutations in Q1 and E1 are associated with cardiac arrhythmia and deafness.The number of E1 subunits in I Ks channels has been a longstanding matter of disagreement. We first argued for two E1 subunits per channel based on the suppression of current by an E1 mutant (18). Subsequently, we reached the same conclusion by determining the total number of channels using radiolabeled charybdotoxin (CTX), a scorpion toxin that blocks channels when one molecule binds in the external conduction pore vestibule, and an antibody-based luminescence assay to tally E1 subunits (19). Morin and Kobertz (20) used iterative chemical linkage between CTX in the pore and E1, and they also assigned two accessory subunits to >95% of I Ks channels without gathering evidence for variation in subunit valence. Furthermore, when we formed I Ks channels from separate E1 and Q1 subunits and compared them with channels enforced via genetic encoding to contain two or four E1 subunits (19), we observed the natural I Ks channels to have the same gating attributes, small-molecule pharmacology, and CTX on and off rates (a reflection of pore vestibule structure) as channels encoded with two E1 subunits but not those with four. These findings support the conclusion that two E1 subunits are necessary, sufficient, and the normal number in I Ks channels.In contrast, others have argued that I Ks channels have va...

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MPS-1 is a K+ channel β-subunit and a serine/threonine kinase

Cited by 31 publications

References 42 publications

Neuromodulators, Not Activity, Control Coordinated Expression of Ionic Currents

Neuromodulators, Not Activity, Control Coordinated Expression of Ionic Currents

A New Mode of Regulation of N-type Inactivation in a Caenorhabditis elegans Voltage-gated Potassium Channel

Individual I _Ks channels at the surface of mammalian cells contain two KCNE1 accessory subunits

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MPS-1 is a K+ channel β-subunit and a serine/threonine kinase

Cited by 31 publications

References 42 publications

Neuromodulators, Not Activity, Control Coordinated Expression of Ionic Currents

Neuromodulators, Not Activity, Control Coordinated Expression of Ionic Currents

A New Mode of Regulation of N-type Inactivation in a Caenorhabditis elegans Voltage-gated Potassium Channel

Individual I Ks channels at the surface of mammalian cells contain two KCNE1 accessory subunits

Contact Info

Product

Resources

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Individual I _Ks channels at the surface of mammalian cells contain two KCNE1 accessory subunits