The MinK-related peptides

doi:10.1016/j.neuropharm.2004.06.018

Neuropharmacology

Volume 47, Issue 6, November 2004, Pages 787-821

https://doi.org/10.1016/j.neuropharm.2004.06.018 Get rights and content

Abstract

Voltage-gated potassium (Kv) channels mediate rapid, selective diffusion of K⁺ ions through the plasma membrane, controlling cell excitability, secretion and signal transduction. KCNE genes encode a family of single transmembrane domain proteins called MinK-related peptides (MiRPs) that function as ancillary or β subunits of Kv channels. When co-expressed in heterologous systems, MiRPs confer changes in Kv channel conductance, gating kinetics and pharmacology, and are fundamental to recapitulation of the properties of some native currents. Inherited mutations in KCNE genes are associated with diseases of cardiac and skeletal muscle, and the inner ear. This article reviews our current understanding of MiRPs—their functional roles, the mechanisms underlying their association with Kv α subunits, their patterns of native expression and emerging evidence of the potential roles of MiRPs in the brain. The ubiquity of MiRP expression and their promiscuous association with Kv α subunits suggest a prominent role for MiRPs in channel dependent systems.

Introduction

Voltage-gated potassium (Kv) channels constitute a highly diverse family of ion channels found in virtually all mammalian cells. They play a key role in governing resting membrane potential and in active membrane repolarisation. Their diversity originates partly from the large number of genes that encode K⁺ channel α subunits, but also from alternative splicing, heteromeric assembly of pore-forming α subunits, RNA editing and post-transcriptional modifications. This multiplicity—manifest as a wide variability in trademark characteristics such as gating kinetics, conductance, ion selectivity and pharmacology—is augmented by the interaction of K⁺ channels with numerous ancillary proteins or β subunits. The concept of Kv α subunits as self-sufficient, channel-forming proteins has been gradually eroded since the cloning of the first cytoplasmic β subunits and we now envisage Kv channels as heteromeric complexes comprised of several types of protein, some membrane-spanning and some cytoplasmic, that function as one to mediate channel trafficking, gating, conduction, regulation and pharmacology. This is not to say that Kv α subunits cannot function alone, but researchers now question whether they ever do function alone in vivo. Results from bilayer recordings of purified protein still support the notion that α subunits are necessary and sufficient for voltage-gated channel function, as do heterologous overexpression experiments, although one can always argue that in the latter case native modifiers allow introduced α subunits to function (see Section 7). Irrespective of whether or not Kv channels ever exist as homomers in vivo, ancillary subunits are clearly anything but bit-players in generating the vast diversity of Kv currents necessary for the function of higher animals. One particular group of ancillary subunits, the MinK-related peptides (MiRPs) encoded by the KCNE gene family, has come to the fore recently because of their demonstrated necessity in human physiology: genetic studies have shown that mutations in three of the KCNE genes associate with human disease. MiRPs are present throughout evolution as modifiers of Kv α subunits in nematodes through to mammals. This review describes our current understanding of the mechanisms by which MiRPs interact with potassium channel α subunits, the spectrum of interactions reported to date and the implications of these interactions to both physiology and pathophysiology.

Section snippets

Ion channel pore-forming (α) subunits

Voltage-gated potassium (Kv) channels assemble as a tetramer of α subunits to form an aqueous, ion-conducting pore in the plasma membrane (Fig. 1A). This is in contrast to voltage-gated sodium and calcium channels, which share a superficially similar channel architecture that consists of four covalently linked repeating units encoded by a single continuous gene (Fig. 1A). This similarity has led to speculation that sodium and calcium channels arose from a progenitor Kv channel gene. Indeed, Kv

The KCNE gene family

There are five known members of the human KCNE gene family, all of which have been assigned at least one possible functional role. The founding member, MinK (minimal K⁺ channel protein, also named IsK), is coded for by the KCNE1 gene and was identified in 1988 by its ability to form a slowly activating potassium current, resembling native K⁺ currents previously observed in cardiac and uterine muscle, when fractionated rat kidney RNA was injected into Xenopus oocytes (Takumi et al., 1988).

The structure of MiRPs and MiRP-α subunit complexes

Human MinK and related peptides (MiRPs) are integral membrane proteins, 103–177 residues in length, their single TM domain flanked by an extracellular N-terminal and cytosolic C-terminal (Fig. 2, Fig. 3). MiRPs cannot form functional ion channels alone, however when co-expressed with pore forming Kv α subunits or those exhibiting structural homology, they form stable complexes and serve to modulate important biophysical properties of the channel. The stoichiometry and exact location of MiRPs

Mechanisms underlying KCNE control of Kv channel α subunits

Following the cloning of MinK, a detailed investigation into the mechanism by which this protein interacts with KCNQ1 was carried out using site-directed mutagenesis, revealing a strong reliance on the membrane-proximal C terminus of MinK for function (Takumi et al., 1991). Later, D76N, a C-terminal mutation associated with inherited LQT syndrome, was shown to strongly reduce I_Ks current in a dominant negative fashion, largely by reducing unitary conductance (Splawski et al., 1997, Sesti and

MinK/MiRPs interact promiscuously with numerous Kv channel α subunits

The functional interactions of MinK/MiRPs with a variety of K⁺ channel α subunits and the mechanism by which MinK/MiRPs exert their effects have been studied primarily in heterologous expression systems such as Xenopus laevis oocytes and in mammalian cell lines such as CHO (Chinese hamster ovary), HEK293 (human embryonic kidney) and COS-7 (Cercopithecus aethiops kidney fibroblasts).

Xenopus oocytes express endogenous MinK/MiRPs

Disparities in the literature suggest that MiRP subunits may modulate the gating of a particular α subunit type differently when expressed in Xenopus oocytes compared to in mammalian expression systems. For example, in CHO cells MiRP2 shifts the half-maximal voltage dependence of Kv3.4 activation by −45 mV and also causes a 30-fold reduction in sensitivity to blockade by BDS-II, a peptide toxin from the sea anemone Anemonia sulcata; in oocytes only subtle changes in voltage dependence of

MinK/MiRPs are widely expressed in mammalian tissues

The diverse expression of MinK/MiRPs in a wide range of tissues across a variety of species, including humans, is one of many findings that indicate an important role for these ancillary proteins in cell physiology. This section of the review summarises the existing evidence for the native expression of MinK and MiRPs (Table 2). Findings are grouped into heart, smooth muscle and epithelia, skeletal muscle, and brain.

All five MiRPs have been detected in cardiac tissue at the mRNA level and three

The physiological and pathophysiological importance of MiRPs

In this section, we highlight the importance of MiRPs in channel-dependent systems. We discuss research aimed at bridging the gap between expression-clone studies and native function by addressing three fundamental questions (Abbott et al., 2001b): (1) Are the subunits co-expressed in the same native tissue, in complexes or otherwise, as assessed at mRNA and preferably protein level? (2) When studied in expression systems does the complex recapitulate the properties and pharmacology of native

Conclusions

MiRPs represent a unique class of ion channel ancillary subunits, that modify and often radically alter gating, conductance and pharmacology of Kv α subunits from a variety of subfamilies, and the related HCN K⁺/Na⁺-specific channel α subunits. MiRPs exhibit promiscuity, each interacting with several α subunit types in heterologous expression experiments and perhaps in vivo. Established expression systems express endogenous MiRPs, an important consideration when designing experiments,

Acknowledgements

We are grateful for financial support in the form of a Greenberg Atrial Fibrillation Grant and an American Heart Association Scientist Development Grant (0235069N) to G.W.A.

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The phosphatidyl-inositol-4,5-bisphosphate (PIP₂) lipid has been shown to be crucial for the coupling between the voltage sensor and the pore of the potassium voltage-gated K_V7 channel family, especially the K_V7.1 channel. Expressed in the myocardium membrane, K_V7.1 forms a complex with KCNE1 auxiliary subunits to generate the I_KS current. Here we present molecular models of the transmembrane region of this complex in its three known states, namely the Resting/Closed (RC), the Intermediate/Closed (IC), and the Activated/Open (AO), robustness of which is assessed by agreement with a range of biophysical data. Molecular Dynamics (MD) simulations of these models embedded in a lipid bilayer including phosphatidyl-inositol-4,5-bisphosphate (PIP₂) lipids show that in presence of KCNE1, two PIP₂ lipids are necessary to stabilize each state. The simulations also show that KCNE1 interacts with both PIP₂ binding sites, forming a tourniquet around the pore and preventing its opening. The present investigation provides therefore key molecular elements that govern the role of PIP₂ in KCNE1 modulation of I_KS channels, possibly a common mechanism by which auxiliary KCNE subunits might modulate a variety of other ion channels.
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A recently discovered sudden cardiac arrest (SCA) syndrome is linked to a risk haplotype that harbors the dipeptidyl-peptidase 6 (DPP6) gene as a plausible culprit.
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Citation Excerpt :
In vertebrates, both the Kv channels and the MiRP/KCNE family proteins show a broad expression pattern in various tissues, including heart, uterus, kidney, epithelia, and the nervous system,1 and have been implicated in excitatory properties of the different cell types. In the brain, Kv channels and their ancillary subunits play an important role in a multitude of neural functions, including the generation and regulation of long-term potentiation (LTP).1,3 The C. elegans genome encodes four MiRP/KCNE homolog proteins (mps-1 to mps-4) that are all predominantly expressed in the nervous system.4
Activity-dependent persistent changes in neuronal intrinsic excitability and synaptic strength are underlying learning and memory. Voltage-gated potassium (K_v) channels are potential regulators of memory and may be linked to age-dependent neuronal disfunction. MinK-related peptides (MiRPs) are conserved transmembrane proteins modulating K_v channels; however, their possible role in the regulation of memory and age-dependent memory decline are unknown. Here, we show that, in C. elegans, mps-2 is the sole member of the MiRP family that controls exclusively long-term associative memory (LTAM) in AVA neuron. In addition, we demonstrate that mps-2 also plays a critical role in age-dependent memory decline. In young adult worms, mps-2 is transcriptionally upregulated by CRH-1/cyclic AMP (cAMP)-response-binding protein (CREB) during LTAM, although the mps-2 baseline expression is CREB independent and instead, during aging, relies on nhr-66, which acts as an age-dependent repressor. Deletion of nhr-66 or its binding element in the mps-2 promoter prevents age-dependent transcriptional repression of mps-2 and memory decline. Finally, MPS-2 acts through the modulation of the K_v2.1/KVS-3 and K_v2.2/KVS-4 heteromeric potassium channels. Altogether, we describe a conserved MPS-2/KVS-3/KVS-4 pathway essential for LTAM and also for a programmed control of physiological age-dependent memory decline.
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Mini-reviewThe MinK-related peptides

Abstract

Introduction

Section snippets

Ion channel pore-forming (α) subunits

The KCNE gene family

The structure of MiRPs and MiRP-α subunit complexes

Mechanisms underlying KCNE control of Kv channel α subunits

MinK/MiRPs interact promiscuously with numerous Kv channel α subunits

Xenopus oocytes express endogenous MinK/MiRPs

MinK/MiRPs are widely expressed in mammalian tissues

The physiological and pathophysiological importance of MiRPs

Conclusions

Acknowledgements

Cell

Cell

Mayo Clin. Proc

J. Biol. Chem

Biophys. J

Curr. Opin. Neurobiol

J. Biol. Chem

J. Biol. Chem

Trends Pharmacol. Sci

Neuron

Biochem. Biophys. Res. Commun

Vasc. Pharmacol

Neuron

Biophys. J

Neuron

Neuron

Curr. Biol

J. Biol. Chem

Cell

FEBS Lett

Biochem. Biophys. Res. Commun

J. Biol. Chem

J. Biol. Chem

J. Biol. Chem

Neuron

Gastroenterology

J. Biol. Chem

Cell

FEBS Lett

Med. Clin. North Am

Cell

Neuron

Am. Heart J

Neuron

Neuron

J. Biol. Chem

J. Biol. Chem

J. Biol. Chem

Disease-associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism

FASEB J

Do all voltage-gated potassium channels use MiRPs?

Circ. Res

Heteromeric HCN1–HCN4 channels: a comparison with native pacemaker channels from the rabbit sinoatrial node

J. Physiol

Modulation of A-type potassium channels by a family of calcium sensors

Nature

Pharmacogenetic considerations in diseases of cardiac ion channels

J. Pharmacol. Exp. Ther

A corticosteroid-induced gene expressing an “IsK-like” K+ channel activity in Xenopus oocytes

Proc. Natl. Acad. Sci. USA

A view of sur/KIR6.X, KATP channels

Annu. Rev. Physiol

Delayed rectifier currents in rat globus pallidus neurons are attributable to Kv2.1 and Kv3.1/3.2 K(+) channels

J. Neurosci

K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current

Nature

Excitation–Contraction Coupling and Cardiac Contractile Force

Cellular dysfunction of LQT5-minK mutants: abnormalities of IKs, IKr and trafficking in long QT syndrome

Hum. Mol. Genet

The minK potassium channel exists in functional and nonfunctional forms when expressed in the plasma membrane of Xenopus oocytes

J. Neurosci

Mini-review
The MinK-related peptides