Elsevier

Cell Calcium

Volume 58, Issue 1, 1 July 2015, Pages 79-85
Cell Calcium

Review
Potassium fluxes across the endoplasmic reticulum and their role in endoplasmic reticulum calcium homeostasis

https://doi.org/10.1016/j.ceca.2014.11.004Get rights and content

Highlights

Abstract

There are a number of known and suspected channels and exchangers in the endoplasmic reticulum that may participate in potassium flux across its membrane. They include trimeric intracellular cation channels permeable for potassium, ATP-sensitive potassium channels, calcium-activated potassium channels and the potassium-hydrogen exchanger. Apart from trimeric intracellular cation channels, which are specific to the endoplasmic reticulum, other potassium channels are also expressed in the plasma membrane and/or mitochondria, and their specific role in the endoplasmic reticulum has not yet been fully established. In addition to these potassium-selective channels, the ryanodine receptor and, potentially, the inositol 1,4,5-trisphosphate receptor are permeable to potassium ions. Also, the role of potassium fluxes across the endoplasmic reticulum membrane has remained elusive. It has been proposed that their main role is to balance the charge movement that occurs during calcium release and uptake from or to the endoplasmic reticulum. This review aims to summarize current knowledge on endoplasmic reticulum potassium channels and fluxes and their potential role in endoplasmic reticulum calcium uptake and release.

Introduction

There are a number of known and suspected channels and exchangers in the endoplasmic reticulum (ER) membrane that may mediate potassium flux through the ER membrane. They include the potassium permeable trimeric intracellular cation channels (TRIC channels), ATP-sensitive and Ca2+-activated potassium channels (KATP and KCa channels, respectively), most abundant in the plasma membrane but found also in the mitochondrial inner membrane, the mitochondrial potassium-hydrogen exchanger (KHE) and, potentially, the ryanodine receptor (RYR) and inositol 1,4,5-trisphosphate receptor (IP3R) ER Ca2+ release channels both permeable for potassium. Apart from the TRIC channels, which are found only in the ER, the functionality of potassium channels in the ER has remained unclear. These channels are assembled in the ER and then transported to the Golgi apparatus and from the Golgi apparatus to their final destination on the cell surface or elsewhere. It is therefore difficult to establish whether these channels play a functional role in the ER membrane. Nevertheless, there is evidence that some of these channel isoforms/subunits tend to be expressed relatively robustly in the ER compared with other cell structures. The role that potassium fluxes play across the ER membrane has also remained elusive. It has been proposed that their main role is to balance the charge movement that occurs during Ca2+ release and uptake from or to ER. Here, we summarize current knowledge on ER potassium channels and fluxes and their potential role in ER Ca2+ uptake and release.

Section snippets

Ca2+ movement across the ER membrane requires counter-ion flux

The ER (or sarcoplasmic reticulum, SR, in muscle cells) serves as a dynamic Ca2+ store involved in several cell types in fast signaling associated with cell stimulation. As an example, in cardiomyocytes, immediately following depolarization-induced entry of extracellular Ca2+, Ca2+ release from the SR to the cytoplasm initiates cardiomyocyte contraction. Reuptake of this Ca2+ into the intra-reticular space then leads to relaxation of the cell. In neurons, Ca2+ is released from the ER during

Trimeric intracellular cation channels

In 2007, Yazawa et al. [16] discovered trimeric intracellular cation channels (TRIC) located in the ER/SR. They identified two TRIC isoforms, TRIC-A, which is expressed predominantly in the reticulum of muscle cells, and the ubiquitously expressed TRIC-B. Further reconstitution experiments have demonstrated that both proteins form voltage-dependent cation channels, permeable to K+ and Na+ but not to divalent cations or anions. Both TRIC-A and TRIC-B function as K+-permeable channels with

ATP sensitive KATP channels

The ATP-sensitive K+ channel is an octameric complex comprised of four pore-forming Kir6.X subunits, from the inward rectifier potassium channel family, that are surrounded by four regulatory sulfonylurea receptors (SURs) [24]. ATP binds Kir6.X, thus the channel contains 4 potential binding sites that inhibit its activity [24], [25]. In mammals, there are 2 pore-forming Kir6.X subunits: Kir6.1 (also known as KCNJ8) and Kir6.2 (KCNJ11) [26], [27], [28]. The regulatory SUR subunits are encoded by

Calcium-activated potassium channels

Calcium-activated potassium channels are divided into big conductance Ca2+-sensitive K+ (BKCa), intermediate conductance Ca2+-sensitive K+ (IKCa) and small conductance calcium-sensitive K+ (SKCa) channels based on their K+ conductance (for review see [47]). BKCa channels are activated by membrane depolarization and/or elevated cytosolic Ca2+ [48], [49]. In contrast, SKCa and IKCa channels are voltage insensitive and gated only by increases in cytosolic calcium [50], [51], [52]. Both BKCa and SK

Potassium-hydrogen exchanger

LETM1 (leucine zipper-EF hand-containing transmembrane 1) is a highly conserved eukaryotic protein of the mitochondrial inner membrane that has been proposed to mediate mitochondrial K+–H+ exchange [77], [78], [79], [80], [81]. It is essential for mitochondrial volume homeostasis because the H+ gradient that drives electrophoretic K+ uptake requires electroneutral K+–H+ exchange to prevent mitochondrial K+ accumulation [82], [83] (see also [84]). Indeed, LETM1 inactivation causes severe matrix

Ryanodine and IP3 receptors

Ryanodine receptors (RYRs) are located in the ER/SR membrane and are responsible for the release of Ca2+ from the sarcoplasmic/endoplasmic reticulum in excitable cells, such as different muscle cells and neurons. In cells of striated muscle, release occurs via coupling to the dihydropyridine receptor, whereas in cardiomyocytes, the primary mechanism is calcium-induced calcium release from the sarcoplasmic reticulum. There are three different RYRs isoforms in mammals: RYR1, primarily expressed

Other roles for ER potassium channels

What other roles, if at all, do ER K+ channels play? It is unlikely that the ER, which makes up approximately one tenth of the cell's total volume and has no substantial membrane potential, could store sufficient K+ to affect basal cytosolic K+ levels significantly (∼120–150 mM). The absence of a marked ER transmembrane potential appears to indicate that K+ fluxes across the ER membrane would likely not considerably affect the K+ lumen concentration equilibrated by water flux; thus, [K+] is

Hypothesis

All of this evidence allows the following suggested mechanism of electrical charge balance across the ER/SR membrane (Fig. 2). During the Ca2+ uptake phase, SERCA extrudes two or three protons per two calcium ions pumped into the ER. The extruded protons re-enter via KHE, driving K+ ions out from the ER lumen. Potassium ions, in turn, re-enter the ER via TRIC and/or SKCa channels. Notably, the latter (ER SKCa-s) are under the control of cytoplasmic Ca2+ and may be activated by high cytoplasmic

Conflict of interest

None declared.

Acknowledgements

This work was supported by grants from the Estonian Research Council (IUT2-5) and by the European Regional Development Fund. We also thank Dr. Miriam A. Hickey for her assistance with proofreading.

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