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Biochimica et Biophysica Acta 1857 (2016) 1258–1266
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Biochimica et Biophysica Acta
journal homepage: www.elsevier.com/locate/bbabio
Physiology of intracellular potassium channels: A unifying role as
mediators of counterion fluxes?☆
Vanessa Checchetto a,c, Enrico Teardo a, Luca Carraretto a, Luigi Leanza a, Ildiko Szabo a,b,⁎
a
b
c
Department of Biology, University of Padova, Viale G. Colombo 3, Padova 35131, Italy
CNR Institute of Neuroscience, University of Padova, Viale G. Colombo 3, Padova 35131, Italy
Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, Padova 35131 Italy
a r t i c l e
i n f o
Article history:
Received 17 January 2016
Received in revised form 6 March 2016
Accepted 7 March 2016
Available online 9 March 2016
Keywords:
Potassium channels
Mitochondria
Chloroplast
Nuclear membrane
Bioenergetics
Transcription
a b s t r a c t
Plasma membrane potassium channels importantly contribute to maintain ion homeostasis across the cell membrane. The view is emerging that also those residing in intracellular membranes play pivotal roles for the coordination of correct cell function. In this review we critically discuss our current understanding of the nature and
physiological tasks of potassium channels in organelle membranes in both animal and plant cells, with a special
emphasis on their function in the regulation of photosynthesis and mitochondrial respiration. In addition, the
emerging role of potassium channels in the nuclear membranes in regulating transcription will be discussed.
The possible functions of endoplasmic reticulum-, lysosome- and plant vacuolar membrane-located channels
are also referred to. Altogether, experimental evidence obtained with distinct channels in different membrane
systems points to a possible unifying function of most intracellular potassium channels in counterbalancing
the movement of other ions including protons and calcium and modulating membrane potential, thereby finetuning crucial cellular processes. This article is part of a Special Issue entitled ‘EBEC 2016: 19th European Bioenergetics Conference, Riva del Garda, Italy, July 2–7, 2016’, edited by Prof. Paolo Bernardi.
© 2016 Elsevier B.V. All rights reserved.
1. Introduction
Potassium channels are widely spread over all kingdoms, ranging
from viruses to humans, but the physiological roles they play in the different organisms are not well defined for all of them. A characteristic
feature of highly selective potassium channels is that their preference
for potassium is defined by a conserved amino acid motif, TVGYGD, in
the narrowest stretch of the pore known as the selectivity filter [1,2].
Thus, in principle, a simple bioinformatic analysis can be exploited to
identify putative potassium channels in different organisms with
completely sequenced genomes (see e.g. [3] for prokaryotes). However,
one has to keep in mind that several other channels, which allow the
flux not only of potassium but of other cations as well, do not display
this signature sequence. Yet, under physiological conditions potassium
may be the main cation flowing through them. Notable technical advancement in biophysics and cell biology during the last decades has
led to the discovery of intracellular potassium channels operating in
organelles or in endomembrane systems, even though technical challenges in studying these channels still make their complete
☆ This article is part of a Special Issue entitled ‘EBEC 2016: 19th European Bioenergetics
Conference, Riva del Garda, Italy, July 2–6, 2016’, edited by Prof. Paolo Bernardi.
⁎ Corresponding author at: Department of Biology, University of Padova, Viale G.
Colombo 3, Padova 35131, Italy.
E-mail address: [email protected] (I. Szabo).
http://dx.doi.org/10.1016/j.bbabio.2016.03.011
0005-2728/© 2016 Elsevier B.V. All rights reserved.
characterization difficult: for example ion composition (nature and activity of the ions that are present) on the “extra-cytoplasmic” side of
the organelles or the actual membrane potentials are not always
known [4]. Surprisingly, the presence and function of several K+ channels known to be located in the plasma membrane (PM) has been demonstrated in various, in some cases even in multiple intracellular
membranes as well. Identification of the genes encoding some of these
K+ channel activities has allowed researchers to obtain genetic
evidence regarding both the localization and the patho(physiological)
importance of these non-PM K+ channels. In other cases, determination
of their function relies on (often less clear-cut) pharmacology. In the
present review we give and updated overview of the growing number
of various potassium channels present in intracellular membranes
both in animal and plant cells and discuss their possible functions and
the open questions. Fig. 1 summarizes the currently known localization
of these K+ channels both in plant and animal cells.
2. Mitochondrial potassium channels in animals
Bioenergetics has become central to our understanding of pathological mechanisms as well as the development of new therapeutic strategies and as a tool for gauging disease progression in neurodegeneration,
diabetes, cancer and cardiovascular disease. The view is emerging that
inner mitochondrial membrane (IMM) K+ channels have a profound
effect on mitochondrial function and, consequently, on the metabolic
V. Checchetto et al. / Biochimica et Biophysica Acta 1857 (2016) 1258–1266
Fig. 1. Intracellular potassium channels in plant and animal cells. Intracellular potassium
channels, identified in plant (A) and animal (B) cells in the membranes of the nucleus,
the endoplasmic reticulum, the Golgi apparatus, the mitochondria and peroxisomes.
Channels of the plant-specific chloroplasts and vacuoles as well as of animal cell-specific
lysosomes are also shown. Plant channels are depicted in green, while animal channels
are in red. The channels which have a counterpart also in the plasma membrane are
indicated (found in animal cells). Please see text for details regarding the function of
these proteins. The abbreviations in the figures indicate the following channels. BKCa:
Big conductance calcium-dependent potassium channel; IKCa: Intermediateconductance K+ channel; SKCa Small conductance K+ channel; Kv: voltage-gated
shaker type K+ channels; KATP: ATP-dependent potassium channel (KATP); TASK-3:
two pore potassium channel; Kir: inward rectifier potassium channels; TRIC: trimeric
intracellular cation channels; TMEM175: lysosomal potassium channel; TPKs: two-pore
potassium channels in plants; AtKC1; potassium channel silent subunit; and Castor and
Pollux/DMI1 (does not make infection) potassium channels.
state and survival of the whole cell. IMM channels in general are beginning to emerge as promising oncological targets as well [5]. Disruption
of the sustained integrity of mitochondria is strongly linked to human
disease, and the observed cytoprotective effect of certain IMM K+ channel activators in ischemia/reperfusion and neuronal death models offers
a new perspective concerning the possibility of pharmacological intervention against neurodegenerative diseases. In addition, impaired
coordination between biogenesis and mitophagy, two energy-statedependent processes, is emerging as a key feature of a number of neurodegenerative disorders [6].
Since oxidative phosphorylation requires an electrochemical gradient across the IMM, ion channels in the IMM are also expected to play
an important role in the regulation of energy metabolism. The matrixnegative difference in electrical potential across the IMM (ΔΨm, ranging
between −150 and −180 mV) is maintained by the proton pumps of
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the respiratory chain (RC). Consequently, cations (K+ and Ca2+) flow
from the intermembrane space (where the concentration of ions is
comparable to cytosolic concentrations because the OMM is permeable
to these ions) to the matrix when a permeation pathway opens. The direction of K+ flow has been demonstrated using potassium-specific ionophores such as valinomycin which allow flux of potassium into the
matrix according to the electrochemical gradient [7,8]. The electrically
equivalent anion outflow across ion channels is considered much less
relevant because the pool of small anions in the mitochondrial matrix
is limited compared with the cytosolic K+ pool. To compensate for
charge movement, the RC must increase the rate of proton transfer
from the matrix to the intermembrane space (IMS). To increase RC activity according to the chemiosmotic model, the transmembrane electrochemical proton gradient (Δμ̃H, composed of mainly Δψm) must
decrease. Thus, passive charge flow and Δμ̃H (ΔΨm) are coupled, and
the opening of K+ or Ca2+ channels in the IMM will lead to depolarization. Clearly, this model also functions in reverse; closing cation channels is expected (and observed) to lead to an increase of Δμ̃H (ΔΨm)
(that is, hyperpolarization). Such alterations may in turn have consequences on the rate of superoxide formation. Reactive oxygen species
(ROS) are emerging as key players in the context of pathological conditions (e.g. during tumorigenesis, and neurodegenerative diseases).
Thus, indeed K+ fluxes are expected to influence mitochondrial
oxidative phosphorylation, but contradictory findings exist regarding
possible mechanisms and even the nature and number of potassium
channels operating in the IMM. Given that IMM K+ channels are
encoded by the nuclear genome, the molecular identities of the observed channel activities are still under debate in many (but not all)
cases, as are the mechanisms targeting these proteins to multiple sites
within the cell. IMM K+ channels recorded by patch clamp include
calcium-dependent channels. —Big conductance calcium-dependent
potassium channel (BKCa) [9], Intermediate-conductance calcium-dependent K+ channel (IKCa) [10] and Small conductance calcium-dependent K+ channel (SKCa) [11], voltage-gated shaker type K+ channel
Kv1.3 [12] and the ATP-dependent potassium channel (mitoKATP)
[13]. For this latter channel, the renal outer medullary K+ channel
ROMK2 (Kir1.1b) has been proposed to be the channel-forming subunit
[14], however the molecular components of mitoKATP are still debated
(for recent reviews see [15,16]). Biochemical evidence indicates the
presence of the two-pore potassium channel TASK-3 [17], of Kv1.5
[18], of ROMK2and of Kv7.4 [19] as well. Basically all abovementioned IMM K+ channels identified thus far are considered to be
the mitochondrial counterparts of well-known plasma membrane
(PM) channels and many of them display even multiple subcellular localizations. For example, SKCa has been found to be located in PM, mitochondria and ER as well, where it is essential for Ca2+ uptake by ER in
neurons and cardiomyocytes [20] (see below). Kv1.3 is present in the
PM, in mitochondrial IMM [12], in the cis-Golgi compartment [21] and
in the nuclear membrane system [22] (see below). BKCa is present in
the PM, Golgi, ER and mitochondria [23]. The role of these channels in
the different membranes is only partially established as is(are) the
targeting mechanism(s) allowing their localization to different subcellular compartments. The outstanding question is whether the same protein is sorted to different compartments within the cells or specific
mechanisms account for its localizations. As for mitoBKCa, a recent
study found that this channel in the heart is encoded by a splice variant
of the PM BKCa (KCNMA1-encoded) and harbors a 50-aa splice insert
that is essential for trafficking to the mitochondria [24]. Instead, the proposed mitoKATP component, ROMK2, is a short form of ROMK. To our
knowledge, targeting mechanisms have not been identified for the
other mitochondrial K+ channels, but interestingly, a short sorting
signal in the C-terminal transmembrane domain has been reported to
determine targeting of a viral potassium channel to mitochondria versus PM when expressed in mammalian cells [25] It is important to
underline that not all these intracellular channels have been recorded
in all tissues, but most of their PM counterparts have relatively wide
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tissue-expression profiles. Interestingly, many of these channel activities have been recorded in immortalized cells lines or in cancerous cell
lines, raising the provocative question whether their mitochondrial/intracellular localization might be related to (oncogenic) transformation.
While this possibility cannot be fully excluded, in many cases potassium
channels are active in the mitochondria of healthy tissues.
Due to the lack of molecular identity or to multiple localizations,
unfortunately, studies in this field must contend with a number of important issues, including difficulties in the generation of genetic models
(cells or animals) exclusively lacking the IMM channels. As a matter of
fact, genetic models, which are fundamental to the investigation of the
physiological roles of mitochondrial K+ channels, are largely unavailable. In the case of BKCa, KCNMA1−/− animals have been used, though
these animals also lack the PM BKCa. In KCNMA1−/− cardiomyocytes,
changes in ROS production and an attenuated oxidative phosphorylation capacity were observed, suggesting a mitochondrial role of BKCa
channels in fine-tuning the oxidative state of the cell [26]. Despite the
wide expression and important physiological functions of IKCa, the
absence of this channel protein in transgenic KO mice does not result
in severe physiological changes, possibly because of developmental
compensation [27]. Similarly, in animals lacking Kv1.3, expression of
other Kv channels has been shown to largely compensate for the lack
of Kv1.3 [28]. ROMK-KO mice have been obtained, although they are
short-lived [29]. To the best of our knowledge, no studies have yet
been performed on these animals and in TASK-3 KO mice [30] to assess
mitochondrial function. In summary, the available genetic models target
both the PM and intracellular forms of the channels and are prone to
developmental compensation. The generation of adequate cellular/animal models would allow genetic evidence to be obtained regarding the
relative importance of these channels (which are often co-expressed in
the same tissues) in the regulation of mitochondrial bioenergetics and
of the physiological consequences.
Nevertheless, numerous studies applying pharmacological agents
point to a crucial role of IMM K+ channels in the context of energy
conversion and cellular protection and provide evidence that K +
transport modulates the tightness of coupling between mitochondrial respiration and ATP synthesis. Thus, IMM K+ channels contribute
to the regulation of matrix volume, in addition to influencing ΔΨm
and ΔpH, calcium transport, production of reactive oxygen species
and mitochondrial dynamics. Activation of a mitochondrial
calcium-dependent K+ channel has been proposed to modulate K+
uptake and matrix volume while maintaining mitochondrial membrane potential (ΔΨm) and to confer protection without compromising oxidative phosphorylation during recovery from metabolic stress
[31]. In this case, activation of the channel is proposed to increase
bioenergetic efficiency. Other studies instead indicate that a protective mechanism involving the activation of different IMM K+ channels includes a slight uncoupling effect, i.e., a slight depolarization
leading to increased respiration not coupled to ATP production.
Such uncoupling would decrease energetic efficiency [32]. Similarly,
activity of the evolutionarily conserved ATP-dependent K+ channel
mitoKATP has been linked to ischemic preconditioning, ischemic
postconditioning, and cytoprotection in general [33,34], even though
in heart mitochondria the increased K + influx associated with
mitoKATP opening was able to depolarize the membrane by only
few millivolts [35]. In addition, a recent piece of work demonstrated
that the Kv7.2–7.5 activator retigabine depolarized the mitochondrial membrane potential, decreased mitochondrial Ca2+ levels and in
vivo largely prevented the functional and morphological changes
triggered by global ischemia/reperfusion in Langendorff-perfused
rat hearts, even though ROS production was increased [19]. The
exact basis of K+ channel openers' (KCO) cytoprotective properties
still remains to be elucidated, although it is suggested that 1) attenuation of ROS production in mitochondria may play a significant role;
2) activation of mitoK+ channels controls matrix volume, preserving
a narrow intermembrane space, necessary for efficient oxidative
phosphorylation; and 3) opening of mitoK + channels produces a
mild decrease of membrane potential, thus reducing uptake of
Ca2+ into the mitochondrial matrix, leading to avoidance of Ca2+overload and subsequent permeability transition pore opening. As
mentioned above, most of these studies employed isolated mitochondria and/or relied on the use of non-specific inhibitor or activator drugs displaying pleiotropic effects. The second consideration is
especially true for the mitochondrial KATP channel: the bulk of the
evidence supporting the involvement of this channel in protection
against ischemic/reperfusion damage is pharmacological [36] (see
also review by Szewczyk and colleagues, this issue). Unfortunately,
other cellular targets possibly accounting for the observed effects
have been identified and most, if not all, of the pharmacological
agents reportedly activating mitochondrial KATP can behave as
membrane-permeable weak acid/base pairs, and thus as uncoupling,
Δμ̃H-dissipating agents, possibly accounting for their protective effects. But specificity issues apply also to the other KCOs. For example,
the CGS7184(ethyl1-[[(4-chlorophenyl)amino]oxo]-2-hydroxy-6trifluoromethyl-1H-indole-3-carboxylate), a synthetic BKCa channel
opener, directly activates the ryanodine receptor calcium release
(RYR2) channel in the sarcoplasmic reticulum [37].
Besides a role in cytoprotection, modulation of mitochondrial K+
channels can also lead to cell death and to regulation of autophagy.
Recently it has been reported that in vascular smooth cells Angiotensin
II increased ROS production and autophagy while inhibitors of mitochondrial KATP channels contrasted both events [38]. The example
studied in most detail in the context of cell death is the mitochondrial
Kv1.3 channel. MitoKv1.3 mediates an inward potassium flux to the
mitochondrial matrix and likely has a role in the organellar K+ cycle
that participates in the modulation of coupling between ATP synthesis
and mitochondrial respiration [39]. In vivo evidence has been obtained
suggesting that modulation of mtKv1.3 by pharmacological means
represents an unconventional but promising strategy to selectively
eliminate cancer cells. Kv1.3 is overexpressed in various cancer tissues/cells and expression of PM-located Kv1.3 seems to correlate with
that of the mitochondrial counterpart (mitoKv1.3). MitoKv1.3 was identified as a novel target of Bax: physical interaction between the two proteins via K128 of Bax took place in apoptotic cells, leading to inhibition
of channel activity [40,41] and consequent ΔΨm changes, increased ROS
production and cytochrome c release, whereas Kv1.3- deficient mitochondria were resistant. In agreement with these results, Psora-4,
PAP-1 and clofazimine, three distinct membrane-permeant inhibitors
of Kv1.3 [42], induced death in multiple human and mouse cancer cell
lines by triggering the same series of events. In contrast, membraneimpermeant, selective and high-affinity Kv1.3 inhibitors ShK or
Margatoxin did not trigger apoptosis, suggesting a crucial role for the
mitochondrial Kv1.3 versus PM Kv1.3. Genetic deficiency or siRNAmediated downregulation of Kv1.3 abrogated the effects of the drugs,
proving specificity of their action via Kv1.3. In a preclinical mouse
model, intraperitoneal injection of clofazimine significantly reduced
melanoma tumor size while no adverse effects were observed in several
healthy tissues [43]. Furthermore, these drugs induced death of only the
pathological primary tumor cells from B-cell chronic lymphocytic leukemia patients [44]. As to other IMM K+ channels, inhibition of IKCa by
TRAM-34 increased the sensitivity of melanoma cells to TRAIL treatment [45]. Mitochondrial TASK-3 channels are also likely to contribute
to the regulation of apoptosis since their silencing resulted in compromised mitochondrial function, i.e. mitochondrial membrane depolarization, and reduced cell survival inducing apoptotic cell death in
melanoma cells [46]. Recently a modified channel function of mitochondrial BKCa has been linked to amyloid-beta (Aβ)-induced neuronal
toxicity [47]. In summary, as a result of the above difficulties in the
field, the relationship between mitochondrial ion transport and diseases
linked to altered mitochondrial function is still only partially explored,
but the so-far available data point to IMM K+ channels as possible
targets for therapeutic application against various pathologies.
V. Checchetto et al. / Biochimica et Biophysica Acta 1857 (2016) 1258–1266
3. Mitochondrial potassium channels in plants
Mitochondria in plants are not only the site of respiration and metabolic processes typical of animals, but are in charge of a specialized
plant-specific process, the photorespiration [48]. This process serves to
recycle metabolic products formed during the assimilation phase, due
to the oxygen-fixing ability of the carbon-fixing enzyme Rubisco, and
involves chloroplasts, peroxisomes mitochondria and the cytosol. In
particular, O2 fixation by Rubisco leads to the generation of one molecule 3-phosphoglycerate and of one molecule 2-phosphoglycolate.
This latter metabolite inhibits important enzymes, thus must be detoxified via photorespiration which yields CO2 [49]. Thus, in plants, mitochondria, by impacting on photorespiration, may alter photosynthetic
efficiency as well. Several ion channel activities have been recorded in
plant mitochondria, mostly using the electrophysiological planar lipid
bilayer technique and isolated membrane vesicles (for recent review
see [50]). Among potassium channels, an ATP-regulated potassium
channel (pmitoKATP channel), a large-conductance Ca2+-insensitive
iberiotoxin-sensitive potassium channel, and a large conductance,
calcium-activated, iberiotoxin-sensitive potassium channel (pBKCa)
have been identified [51,52]. Classical bioenergetic studies identified
also other mitochondrial potassium channels, including a cyclosporine
A-activated and ATP-inhibited mitochondrial potassium channel [53]
and a quinine-inhibited but ATP-insensitive potassium channel [54].
Characteristics of the pmitoKATP have been investigated in depth also
using classical bioenergetics (e.g. [55,56], for recent review see [57]).
Similarly to the animal mitoKATP, the plant channel has also been
shown to affect ΔΨm and ROS production. According to the current
view, when ATP inhibits pmitoKATP, ΔΨm remains low
(hyperpolarized) and ROS production is high. PmitoKATP would act as
one of the dissipative systems that may allow influx of positive charges
into the matrix and thus partially depolarize ΔΨm in order to avoid excessive ROS production under environmental stresses. Indeed, determination of the in vivo dynamics of the membrane potential in individual
mitochondria in plants has demonstrated that these organelles undergo
rapid and reversible partial dissipation and restoration of ΔΨm [58]. A
similar situation has been described for pBKCa, i.e. activation of the
channel by Ca2+ and NS1619 stimulated resting respiratory rate and
caused partial mitochondrial membrane depolarization, while the opposite effects could be observed upon inhibition by iberiotoxin [51].
In summary, the original hypothesis [59,60] which predicts that
dissipative pathways, including opening of mitochondrial potassium
channels in the IMM leading to a slight depolarization, would cause
mild uncoupling and a consequent reduction in further mitochondrial
ROS generation according to a feedback mechanism, seems to apply to
both the animal and plant systems, although to different extents
depending on the examined species. It also has to be stressed that the
genetic evidence obtained so far is not sufficient to prove or negate
this idea either in plants or in animals.
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membrane potential across this membrane reaches ~ 100 mV (inside
negative). This H+ extrusion is supposed to be balanced by K+ influx
across the cation selective channels mentioned above.
Such a counterbalancing role has been hypothesized [67] also for the
cation channels detected by electrophysiological studies in the thylakoid membrane [68–71]. Like respiration, photosynthesis leads to the
generation of a proton motive force, composed of a proton gradient
(the ΔpH) and of an electric field (the ΔΨ). Generation of ΔpH is the result of chloroplast lumen acidification following plastoquinol (PQH2)
oxidation by the cytochrome b6f complex and water oxidation by Photosystem II (PSII). The ΔΨ is instead the result of charge separation in PSII
and PSI and of the activity of the cytochrome b6f complex [72]. The ATP
synthase-ATPase CF0_Fi complex translocates H+ and thus modifies the
ΔΨ and ΔpH at the same time, but cannot change the relative composition of the pmf [73]. Instead, ion channels are expected to modify the
ΔΨ/ΔpH ratio, by varying the electric field without directly affecting
the proton gradient. Thus, a partial dissipation of ΔΨ either by cation
efflux from or by anion influx into the thylakoid lumen might ensure
further entry of the positively charged protons therefore contributing
to the establishment of ΔpH. Importantly, the photoprotective mechanism known as non-photochemical quenching (NPQ) which is crucial
for dissipation of excess absorbed light, is triggered by ΔpH (acidic pH
in the lumen) and ΔpH modulates also the rate of electron transfer.
The first genetic proof in favor of the counterbalance hypothesis has
been obtained in cyanobacteria, in which the voltage-gated potassium
channel SynK was found to be located in the thylakoid membrane
[74]. Its lack in knock-out organisms was shown to affect ΔpH, ultimately leading to decreased growth under high light culturing conditions
[75]. Later, the two-pore potassium channel TPK3 was reported to
play a similar role: silenced plants lacking AtTPK3 grown at a light
intensity that was fully tolerated by WT plants, exhibited a decreased
rosette size and an increased light sensitivity as assessed by measuring
photosynthetic parameters and anthocyan content. TPK3 is not voltagegated but it becomes activated by increasing calcium concentration and
acidic pH. In the case of TPK3, using Arabidopsis plants, it was possible to
evaluate the pmf partitioning using the electrochromic shift methodology which is based on the observation that ΔΨ induces a shift in the
absorption spectra of some photosynthetic pigments [76,77]. Thus, the
phenotype reflected the observed altered pmf partitioning, i.e. higher
ΔΨ and lower ΔpH due to the lack of counterbalancing flux of positively
charged potassium ions. This, in turn resulted in reduced CO2 assimilation, reduced growth and also in a deficient NPQ [78]. In contrast, the
KEA3 K+/H+ exchanger was shown to balance the ΔpH and ΔΨ during
transient light shifts and in the dark, when the K+ and H+ gradients
return to the situation preceding illumination [79,80]. Overall, these
studies have opened a novel, fast-developing field of investigation: the
fine-tuning of photosynthesis by ion homeostasis [81]. To complete
these studies several questions have to be answered, first of all regarding the identification of further ion channels mediating the fluxes of
anions and divalent cations in the thylakoid membrane.
4. Chloroplast potassium channels
5. Nuclear potassium channels in animals
Several potassium-selective ion channels with different conductance and characteristics have been recorded from the outer envelope,
inner envelope and thylakoid membranes of chloroplasts as summarized in comprehensive and thorough reviews (e.g. [50,61–64]. Unfortunately, pharmacological characterization of these channels is rather
limited. In addition, patch clamping chloroplasts from the completely
sequenced Arabidopsis model plants represent a so-far unsurmounted
technical difficulty. Therefore, the proteins giving rise to most activities
are undefined. Nonetheless, an important function has been proposed
in the regulation of stroma alkalinization via counterbalance of H+
movement across the inner envelope membrane, especially for an
ATP-sensitive potassium channel [65] and for the fast-activating cation
channel of the envelope membrane [66]. During illumination, due to
H+ pumping by the ATPase of the inner envelope membrane, the
Although various ion channels are present and functional in the
outer and inner nuclear envelope membranes as assessed by biochemical and electrophysiological methodologies (for review see e.g. [82,
83]), surprisingly little is known about their function. The outer nuclear
membrane is continuous with the endoplasmic reticulum so that the
perinuclear space of the nuclear envelope is contiguous with the
lumen of the endoplasmic reticulum. The perinuclear space (nuclear
envelope lumen) is assumed to be the Ca2+ store, generating a concentration gradient across the inner nuclear envelope with high Ca2+ levels
in the nuclear envelope lumen and low Ca2+ levels outside (i.e. in the
nucleoplasm and in the cytosol). The ion gradient for K+ across the
nuclear envelope is not known in intact cells, but studies in isolated
nuclei indicate that the K+ concentration in the perinuclear space is
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much lower than in the cytoplasm and nucleoplasm [84]. Therefore, it is
expected that the changes in the nuclear K+ channel activity would
alter the flux of this cation, leading to an alteration of the nuclear ΔΨ.
The electrical potential difference across the nuclear envelope is the result of various factors comprising intranuclear electrical charges, diffusion of ions across the inner and outer nuclear membranes and
diffusion along the nuclear pore complex and may reach −30 mV (negative inside the nucleus) [83].
More than ten years ago a seminal paper demonstrated the presence
of a functional KATP channel in the nuclei of beta pancreatic cells and
linked glucose metabolism to nuclear Ca2+ signals and nuclear function.
In particular, the authors provided evidence that pharmacological
blockade of the KATP channel in isolated nuclei triggered nuclear Ca2+
transients and induced phosphorylation of the transcription factor
cyclic AMP response element binding protein CREB. Indeed, as was
shown for the first time in hippocampal neurons, signaling to CREB
can be activated by nuclear calcium alone and does not require import
of cytoplasmic proteins into the nucleus [85]. In intact pancreatic cells,
fluorescence in situ hybridization revealed also that these Ca2+ signals
were able to elicit c-myc expression [86]. A similar role has been
envisioned for the BKCa channels, detected in the nuclear envelope of
rodent hippocampal neurons: their blockade was shown to induce
nucleus-derived Ca2+ release, nucleoplasmic Ca2+ elevation and
CREB-dependent transcription and to regulate nuclear Ca2+-sensitive
gene expression. To our knowledge, this important work established
for the first time a link between a nuclear potassium channel and
neuronal activity, also using a genetic model (Kcnma1−/− mice) [87].
Finally, recent evidence indicates that a shaker-like Kv channel, Kv1.3,
has also a nuclear localization besides being active in the PM and in
mitochondria (see above). Kv1.3 channels were found to be expressed
in the nuclei of various cancer cells but also of normal human brain
tissues [22]. The authors reported that the selective Kv1.3 blocker
Margatoxin was able to induce hyperpolarization of the nuclear membrane in isolated nuclei suggesting functional expression. Furthermore,
addition of a membrane-permeant Kv1.3 inhibitor, PAP-1, to intact lung
adenocarcinoma cells resulted in an increased phosphorylation of CREB
and of c-Fos, an immediate early response transcription factor. The
channel was also shown to form a complex with the upstream binding
factor 1 in the nucleus. Interestingly, these authors reported that other
Kv channels, namely Kv1.1, Kv1.2 and Kv2.2 displayed either prevalent
nuclear or mainly PM localization depending on the cancer cell line used
for their studies [22].
Other reports also point to a nuclear localization of channels that are
normally known to be expressed in the PM. For example, immunohistochemical staining of endobronchial biopsies from healthy subjects
revealed that KCa3.1 channels are localized in the plasma membrane
and nucleus of airway smooth muscle cells. However, it is still unclear
whether it is the nuclear or the PM channel whose inhibition by membrane permeant inhibitor TRAM-34 causes enhanced corticosteroid activity in severe asthma [88]. In another study the inward rectifying
Kir2.2 was found in the nucleus in sections of rat hindbrain and dorsal
root ganglia tissue, but again, the functional importance of this localization is unknown [89].
A few years ago, a surprising localization of the human ether à-gogo1 protein (Eag1 or Kv10.1), has been described in the inner nuclear
membrane in both human and rat models [90,91]. Kv10.1 is a member
of the voltage-gated potassium channels (subfamily H) and its peculiarity is that it was the first ion channel demonstrated to have oncogenic
properties, since transfection of Kv10.1 into mammalian cells conferred
a transformed phenotype and favored tumor progression in vivo [92,93].
Kv10.1 is not detected in healthy tissues except the brain, but its overexpression has been detected with a very high incidence (N75%) in several
human malignancies, including glioblastoma, colorectal and cervical
cancer, soft tissue sarcomas, acute myeloid leukemia, esophagus and
gastric cancer [94,95]. High Kv10.1 expression is associated with poor
prognosis in fibrosarcoma, ovarian carcinoma, acute myeloid leukemia
(AML), in colon, head and neck cancer [94]. An increased expression
of Kv10.1 is correlated with downregulation of microRNA miR-296-3p
as observed in glioblastoma [96] and is controlled also by the p53
tumor suppressor-miR-34-E2F1 transcription factor pathway [97].
Overexpression of Kv10.1 promotes cancer cell migration and proliferation by interactions with various proteins, including cortactin and focal
adhesion kinase (FAK), as well as through regulation of calcium signaling [94].
Interestingly, Kv10.1 channels were shown to regulate intracellular
signaling pathways independently of their ability to mediate ion flux
[98,99] and a mutation that abolished potassium permeability did not
prevent tumor formation by transfected cells in vivo [100], suggesting
that channel function is not mandatory for the oncogenic potential of
Kv10.1. These findings are in line with the observations that the majority of Kv10.1 protein remains in intracellular pools, including the
perinuclear region. Interestingly, even if expressed in the plasma membrane, Kv10.1 becomes rapidly (within 30 min) internalized and locates
to the inner nuclear membrane where it is functionally active as
assessed using patch clamping. A conserved nuclear localization signal
is present on the C-terminal cytoplasmic domain of Kv10.1, but this signal does not seem to be required for this localization, which may contribute to the oncogenic properties of the channel by a still unknown
mechanism [101]. The authors hypothesized that the channel may indirectly interact with heterochromatin or may influence gene expression
and genome stability by changing K+ concentration, known to affect the
stability of transcriptional repressor elements (for example of the myc
oncogene) [102].
In summary, several K+ channels, known to reside in the PM, can
reach the nuclear envelope and exert their function there. Most likely
these channel proteins do not follow a route to the nucleus via ER but
via recycling from the PM [101]. This nuclear localization does not
seem to be correlated with pathological conditions; on the contrary,
even in healthy cells it links nuclear membrane potential changes, alteration of nuclear calcium concentration and activation of transcription
factors ultimately leading to changes in gene expression.
6. Nuclear potassium channels in plants
In animal cells, Ca2+-permeable channels such as ryanodine receptors and inositol triphosphate receptors (InsP3R) localized in the nuclear envelope or ER are involved in the generation of Ca2+ oscillations in
the perinuclear region [103]. In plants, in particular in Lotus japonicus
and Medicago truncatula, perinuclear calcium spiking in legume root
symbiosis was shown to require two potassium-permeable channels,
Castor and Pollux in Lotus [104] or their homolog, Does Not Make Infections1 (DMI1) in Medicago [105,106]. Interestingly, Castor and Pollux
have been identified through a screening aiming at identifying genes
involved in the transcriptional reprogramming of the root during symbiosis [107]. The selectivity filter of Castor and Pollux contains the sequence ADSGNHA instead of the classical TVGYGD sequence, while
the M. truncatula Pollux ortholog DMI1 contains ADAGNHA.Castor and
Pollux are not potassium-selective channels, and show only a moderate
preference for K+ over Na+ and Ca2+. Evidence has been gained that
Castor and Pollux (and DMI1 alone in Medicago) modulate the nuclear
envelope membrane potential and thereby either trigger opening of nuclear calcium release channels and/or compensate the charge release
during the calcium efflux as counter ion channels. In particular, the
Parniske group suggested the following model: DMI1 or Castor and
Pollux together would be required to mediate the flux of K+ ions
along their concentration gradient from the cytoplasm to the
perinuclear space. This sustained flow would lead to subsequent rapid
hyperpolarization of both nuclear membranes which is required to activate the nuclear Ca2+ channel. Ca2+ then flows out of the perinuclear
space to the cytoplasm, giving rise to a Ca2+ spike. The DMI1 and
Castor/Pollux cation channels, upon sensing the Ca2+, would be blocked
or inactivated. Simultaneously, the Ca2+ flow would reduce the
V. Checchetto et al. / Biochimica et Biophysica Acta 1857 (2016) 1258–1266
hyperpolarization of the nuclear membranes, resulting in the closure of
hyperpolarization-activated Ca2+ channels. Finally, the Ca2+ ions would
be pumped back into the perinuclear space (the calcium store), by the
Ca2+ ATPase bringing the membrane back to its resting potential,
ready to reinitiate the cycle. In summary, these plant nuclear channels
would act as counter-ion channels that compensate for the positive
charge associated with Ca2+ release during perinuclear calcium spiking
[108].
7. SR/ER/golgi-located and lysosomal potassium channels
Ca2+ release from the intracellular stores sarco/endoplasmic reticulum (SR/ER) crucially regulates cellular functions including muscle
contraction, gene transcription, secretion and cellular metabolism.
When Ca2+ is released from the SR/ER, a negative potential would be
generated on the SR/ER luminal side as a result, and this would be expected to inhibit subsequent Ca2+ release. On the other hand, the generation of a positive potential within the SR/ER lumen during Ca2+
uptake would tend to inhibit Ca2+-pumping function. It is therefore
likely that potent counter-ion movements (for example via potassiun
channels) are essential to balance the SR/ER membrane potential and
maintain efficient Ca2+ release/uptake from/into this intracellular calcium store [109,110]. The role of functional potassium channels in the
Golgi (e.g. Kv1.3 [21]) is less intuitive.
Numerous potassium channels have been described in the endo/sarcoplasmic reticulum (for recent review see [111]). Among these, KATP
[112], SKCa [20] and the voltage-gated K+ channel Kv1.6 [21] are likely
counterparts of the PM channels, while the trimeric intracellular cation
(TRIC) channels [113] which are also permeable to potassium, represent
a specific intracellular form. For these latter channels it has been clearly
demonstrated in an elegant piece of work that TRIC is required for K+
permeability of the skeletal muscle sarcoplasmic reticulum, as well as
for correct Ca2+ signaling. TRIC-knockout mice suffered from embryonic
cardiac failure and mutant cardiac myocytes showed severe dysfunction
in intracellular Ca2+ handling. Thus, this work provided compelling evidence that TRIC channels are likely to act as counter-ion channels that
function in synchronization with Ca2+ release from intracellular stores
[113]. A similar conclusion has been reached in neurons and
cardiomyocytes in another investigation, whose authors reported that
inhibitors of SKCa channels blocked the uptake of Ca2+ by the ER,
whereas inhibitors of IKCa, BKCa and KATP had no effect [20]. What is
the relative contribution of TRIC and SKCa in cardiomyocytes to charge
counterbalancing and whether one of the two channels may prevail
depending on different (patho)physiological conditions, are still open
questions.
In plants, to our knowledge, no potassium channel with such a function has been identified. AtKC1, a silent Arabidopsis potassium channel
alpha subunit, which is reportedly not able to form functional ion
channel on its own [114], was shown to reside in the ER unless it is
co-expressed with other shaker-type inward rectifier subunits, such as
AKT1, KAT1, KAT2 and AKT2 [115]. Only in this case, the shaker alpha
subunit-AtKC1 tetramers, displaying different biophysical properties
with respect to AKT1 or KAT1, KAT2 and AKT2 homotetramers alone, relocate to the plasma membrane [115,116]. Whether the tetramers
formed in the ER are functional and whether they may contribute to
counterbalance during ER calcium release/signaling in plants is still
unexplored.
Just a few months ago, the first protein underlying the lysosomal/
endosomal potassium conductance has been identified [117]: in this
seminal paper, the authors discovered that the potassium channel
recorded by patch clamp directly on the organelle is formed by
TMEM175, a protein with previously unknown function. In the past,
the two-pore potassium channel K2P1 protein has been detected in
endosomes using immunostaining [118], but the measured lysosomal
K+ current was independent of K2P1 expression [117]. Similarly to
Castor, Pollux and DMI1, the protein TMEM175 does not harbor the
1263
typical selectivity filter sequence of K+ channels. Yet, TMEM175 is highly selective for potassium. Lysosomes lacking TMEM175 exhibited no
K+ conductance, had a markedly depolarized ΔΨ and displayed little
sensitivity to changes in [K+]. Interestingly, lack of this protein conferred compromised luminal pH stability, indicating a role for potassium
as counterion to maintain acidic pH in the lumen. Abnormal fusion with
autophagosomes during autophagy also occurred in the KO cells. It is
thus highly likely that this channel will join to the list of lysosomal
channels whose mutation is linked to severe diseases, including neuronal degeneration and lysosomal storage diseases [119,120].
8. Vacuolar plant potassium channels and peroxisomal cation
channels
No osmotic gradient persists across the membrane of plant storageorganelles, the vacuoles, since their membrane is permeable to water. A
large amount of inorganic ions acting as osmolites is accumulated in
plant vacuoles via specific channels and transporters [121–123]. An
electrochemical gradient favoring the efflux of potassium ions from vacuoles towards the cytosol exists. Several K+ channels have been shown
to reside in the membrane of the large central lytic vacuole or of protein
storage vacuoles, all of them belonging to the two-pore potassium TPK
channel family which is comprised of 6 members [124–126]. AtTPK4
is targeted to the PM, while the other members localize to the vacuolar
membrane (but see above TPK3 in the thylakoid). However, the roles of
vacuolar TPKs are still largely unknown [125]. The best characterized
TPK is AtTPK1, whose activity is regulated by calcium, by interaction
with 14-3-3 proteins, by luminal pH [127] and by membrane tension
[128]. Transgenic plants either lacking or overexpressing this channel
highlighted that TPK1 has a function in intracellular K+ homeostasis,
affects germination, seedling growth and stomatal movement [129].
TPK channels have been proposed to underlie the so-called vacuolar
K+ (VK) channel which is highly selective for K+ ions [130,131], is
fast-activating and has thus been postulated to play a major role in
guard cell turgor regulation and K+ homeostasis. VK channels were
proposed to contribute to a calcium-induced calcium release from the
vacuoles, by shifting the resting vacuolar membrane potential (see e.g.
[131]).
In the peroxisomal membrane two proteins, namely Pex11 and
Pxmp2, both giving rise to high conductance channels with slight
preference for cations, have been characterized. The yeast Pex11 poreforming protein shares sequence similarity with transient receptor
potential melastatin (TRPM) cation-selective channels and forms a
voltage-independent channel with a conductance of 4.1 nS in 1.0 M
KCl [132]. The other weakly cation selective channels are formed by
Pxmp2 and display a conductance of 1.3 nS in 1.0 M KCl [133]. Both
proteins have been proposed to mediate the flux of small metabolites
across the peroxisomal membrane.
9. Conclusion
In summary, the number of potassium channel proteins located in
intracellular membranes is rapidly increasing. A part of these proteins
displays a classical selectivity filter sequence in their pore loop, while
novel, unexpected proteins without this signature sequence have also
been identified and shown to function as potassium channels. This finding suggests that in the future, other, atypical proteins might emerge as
potassium channels. The major part of the identified channels are counterparts of the PM-located well-known K+ channels, and some of them
show even multiple localizations within the cells, while other channels
are exclusively located in organelle membranes. Several open questions
will have to be addressed in future studies related to e.g. targeting and
molecular identity, in order to fully appreciate the physiological functions of these ion channels. In addition to ion channels, of course a plethora of potassium-transporting carriers have been described and studied
1264
V. Checchetto et al. / Biochimica et Biophysica Acta 1857 (2016) 1258–1266
in the various membranes, whose function is likely to be wellcoordinated with that of the channels.
Transparency document
The Transparency document associated with this article can be
found, in online version.
Acknowledgments
The authors are grateful to Mario Zoratti for useful discussion and for
critical reading of the manuscript and to the Italian Association for Cancer Research (AIRC grant IG 11814 to IS), to Human Frontiers Science
Program (HSFP RG0052 to IS) and to the Italian Ministry of Education
(PRIN project 2010CSJX4F to IS), for financial support. I.S. is grateful
also to Iontrac Marie-Curie Training Network (FP7-PEOPLE-2011-ITN
Grant Agreement No. 289648). L.L. is a recipient of a Young Investigator
Grant of the University of Padova (GRIC12NN5G).
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