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Ion channels are transmembrane proteins that selectively allow ions to flow across the plasma membrane and play key roles in diverse biological processes. A multitude of diseases, called channelopathies, such as epilepsies, muscle paralysis, pain syndromes, cardiac arrhythmias or hypoglycemia are due to ion channel mutations. A wide corpus of literature is available on ion channels, covering both their functions and their roles in disease. The research community needs to access this data in a user-friendly, yet systematic manner. However, extraction and integration of this increasing amount of data have been proven to be difficult because of the lack of a standardized vocabulary that describes the properties of ion channels at the molecular level. To address this, we have developed Ion Channel ElectroPhysiology Ontology (ICEPO), an ontology that allows one to annotate the electrophysiological parameters of the voltage-gated class of ion channels. This ontology is based on a three-state model of ion channel gating describing the three conformations/states that an ion channel can adopt: closed, open and inactivated. This ontology supports the capture of voltage-gated ion channel electrophysiological data from the literature in a structured manner and thus enables other applications such as querying and reasoning tools. Here, we present ICEPO (ICEPO ftp site:, as well as examples of its use.
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Original article
ICEPO: the ion channel electrophysiology
V. Hinard
, A. Britan
, J.S. Rougier
, A. Bairoch
, H. Abriel
P. Gaudet
CALIPHO Group, SIB Swiss Institute of Bioinformatics, 1 rue Michel-Servet, CH-1211 Geneva 4,
University of Bern, Murtenstrasse 35, CH-3008 Bern, Switzerland and
Department of
Human Protein Science, University of Geneva Medical School, 1 rue Michel-Servet, CH-1211 Geneva 4,
*Corresponding author: Email:, Tel: þ41 22 379 50 50, Fax: þ41 22 379 58 58
Citation details: Hinard,V., Britan,A., Rougier, J.S. et al. ICEPO: the Ion Channel ElectroPhysiology Ontology. Database (2016)
Vol. 2016: article ID baw017; doi:10.1093/database/baw017
Received 6 November 2015; Revised 26 January 2016; Accepted 3 February 2016
Ion channels are transmembrane proteins that selectively allow ions to flow across
the plasma membrane and play key roles in diverse biological processes. A multitude of
diseases, called channelopathies, such as epilepsies, muscle paralysis, pain syndromes,
cardiac arrhythmias or hypoglycemia are due to ion channel mutations. A wide corpus
of literature is available on ion channels, covering both their functions and their roles in dis-
ease. The research community needs to access this data in a user-friendly, yet systematic
manner. However, extraction and integration of this increasing amount of data have been
proven to be difficult because of the lack of a standardized vocabulary that describes the
properties of ion channels at the molecular level. To address this, we have developed Ion
Channel ElectroPhysiology Ontology (ICEPO), an ontology that allows one to annotate the
electrophysiological parameters of the voltage-gated class of ion channels. This ontology
is based on a three-state model of ion channel gating describing the three conformations/
states that an ion channel can adopt: closed, open and inactivated. This ontology supports
the capture of voltage-gated ion channel electrophysiological data from the literature in a
structured manner and thus enables other applications such as querying and reasoning
tools. Here, we present ICEPO (ICEPO ftp site:
trolled_vocabularies/), as well as examples of its use.
Ion channels are pore-forming transmembrane proteins that
selectively allow ions to flow across the plasma membrane
according to electro-chemical gradients. They play key roles
in diverse cellular processes, including nerve and muscle exci-
tation, synaptic transmission, cardiovascular regulation, hor-
mone secretion and sensory transduction. In humans, there
are 344 genes encoding ion channels (1) and mutations
CThe Author(s) 2016. Published by Oxford University Press. Page 1 of 7
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Database, 2016, 1–7
doi: 10.1093/database/baw017
Original article
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in >126ofthesegeneshavebeenassociatedwithdiseases
Disruption of any aspect of ion channel function can
cause a wide spectrum of diseases, known as channelopa-
thies. Approximately 160 human diseases resulting from
mutations in ion channels have been identified (1).
Channelopathies can affect the nervous, cardiovascular, re-
spiratory, endocrine, urinary and immune systems.
Moreover, ion channel malfunction is suspected to have a
role in the pathogenesis of cancer, gastrointestinal or psy-
chiatric disorders (2). In addition, ion channels are the tar-
gets of a myriad of drugs that are used in many clinical
Classes of ion channels
Ion channels can be classified according to either (i) the type
of ions for which they are permeable, (ii) their three dimen-
sional structure (1) or (iii) the type of stimulus that triggers
their activation gating. The stimulus-gated classification can
be further sub-divided based on the specific stimulus that
triggers their activation: changes in membrane potential (or
voltage), ligands, temperature, light and by the stretching or
deformation of the cell membrane (3,4).
Ion channels that open following a change in the mem-
brane voltage potential are known as ‘voltage-gated ion
channels’ (5). ‘Ligand-gated ion channels’ allow ions to flow
across the pore in response to the binding of a chemical mes-
senger (ligand) to the cytoplasmic or extracellular side of the
channel (6). These two families are the most important ones,
with 100 proteins each in human. ‘Temperature-gated ion
channels’ are represented by thermosensitive ion channels
that belong to the Transient Receptor Potential channel fam-
ily. They allow animals to sense hot and cold environment
and react in a suitable manner. The only known natural
‘light-activated ion channels’ are found in green algae
andarenamedchannelrhodopsin-1and-2(7). Finally,
the ‘mechanically gated ion channels’ are ion pore-forming
proteins able to detect mechanical stimulation such as ten-
sion, pressure, stretch and cell volume change. Following
membrane deformation, they open and let ions pass trigger-
ing an appropriate electrochemical response to the stimulus.
There are only five genes in human whose product displays
mechanically gated properties but several other types of ion
channels such as the ligand-gated NMDA receptors or
ENaC proteins can be activated by membrane deflection (8).
The ontology we present focuses on the description of
the biophysical properties of voltage-gated ion channels.
We limited our scope on this class because it is one of
the largest, and the most important one with respect to the
number of genes associated with channelopathies.
Voltage-gated ion channel gating
The gating dynamics of the voltage-gated ion channels in-
clude three main transitions: opening, inactivation and
closing. Opening of the channel pore leads to the flow of
ions through protein according to the electro-chemical gra-
dient existing across the membrane. This opening is regu-
lated by the gating of the pore. In response to changes in
transmembrane electrical potential difference, ion channels
go from a closed state (non-conducting) to an open-state
(permeable to ions) as a result of a conformational change
in the pore. This transition is referred to ‘activation’. For
example, voltage-gated ion channels have a voltage-sensor,
consisting of a collection of charged amino acids that move
under the influence of the membrane electrical field, thus
opening the pore (Figure 1).
Following activation, voltage-gated ion channels go
through an inactivated state during which the channel is
non-conducting and refractory to open, so-called inactiva-
tion (Figure 1). The inactivated state is followed by the re-
turn to the closed state via a transition named recovery
from inactivation. Once in the closed or resting state, the
ion channel can be activated once again and the cycle can
All of these transitions are reversible: the open channel
can revert to the closed state, a transition named deactiva-
tion; it can go from the inactivated state to the open state,
or reopening; and finally, a closed channel can go to the
inactivated state, via closed-state inactivation. These tran-
sitions only happen when the energetic cost and constants
rate are favorable (Figure 1).
Gating kinetics
While the main factor influencing voltage-gated ion channel
gating is the change transmembrane voltage difference, the
molecular dynamics are also dependent on the transition rate
constants also known as gating kinetics. The gating kinetics
are essential in determining the role of each ion channels by
controlling the cellular excitability (9). Most of the voltage-
gated ion channels exhibit delays in their time course, reflect-
ing multiple sub-transition steps between the main states. For
example, after depolarization, voltage-gated ion channels re-
quire several sequential steps involving the movement of the
gating charge to fully open the activation gate. A higher depo-
larized potential accelerates those steps by increasing their
rate constants (10). Moreover, ion channel kinetics are also
dependent on inactivation mechanisms. The open time of an
ion channel depends on the time required to close the inacti-
vation gate. For example, voltage-gated potassium channels
can be divided in two types according to their inactivation
kinetics: the A-type Kþchannels being fast inactivating
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channels and the delayed rectifiers being very slow in their in-
activation (11).
Available ontologies and databases relevant to
ion channel function
Approximately 10 000–15 000 original scientific articles
are published every year on ion channels, covering topics
such as their molecular and cellular characterization, their
pathophysiological roles, as well as new strategies to treat
and/or prevent diseases (12). Like many other genes, the
genes encoding channel subunits have been found to show
an impressive polymorphism. Disease-causing genetic
variants can affect any aspect of the molecular mechan-
isms of ion channel activity. To develop a tool to classify,
analyse and make predictions about ion channel variants,
it is necessary to precisely describe these defects in a struc-
tured data model. We first investigated available re-
sources that describe the biophysical parameters of ion
Gene Ontology (GO) (13), the most widely used con-
trolled vocabulary in biology, hastermsforallclassesofion
channels: voltage-gated ion channel activity (GO:0005244),
ligand-gated ion channel activity (GO:0015276), tempera-
ture-gated ion channel activity (GO:0097603), light-activated
ion channel activity (GO:0010461) and mechanically gated
ion channel activity (GO:0008381). It has also specific terms
for biological processes such as the trafficking or the cluster-
ing of proteins at the plasma membrane. GO molecular func-
tion terms describe activities that occur at the molecular
level, such as ‘catalytic activity’ or ‘binding activity’.
However, GO does not dwell on the details of the biophys-
ical properties of proteins. As explained in the documentation
guidelines), the description of reactions as GO functions does
not split each step of the reaction in different functions that
would describe the atomic or subatomic terms; rather, it con-
siders the starting state and the end state in terms of the mol-
ecules involved. Thus, the level of granularity of GO
functions is not precise enough to capture biophysical proper-
ties of ion channels, such as transition states. The other types
of biological processes impacting the ion channel function
being already described in GO, it is out of the scope of the
NIF (Neuroscience Information Framework), an initia-
tive of the NIH Blueprint (
shtm), groups nearly all the resources covering the current
databases, ontologies and terminologies related to neuro-
sciences. One of the main resources supported by NIF
that caters for neuroscience ontologies is the neuroscience
lexicon: NeuroLex (
This resource covers all the terminologies about neuronal
cell types, brain regions, related diseases, electrophysiolo-
gical protocols and biological processes, all organized in a
consistent hierarchy (14). Channelpedia (http://channelpe is a database developed by the Blue Brain
Project and contains an extensive and comprehensive
amount of ion channel information captured in research
articles (15). IUPHAR, the International Union of basic
and clinical PHARmacology (http://www.guidetopharma focuses on pharmacological targets and
drugs acting on these targets. It captures ion channel fea-
tures including some functional and biophysical charac-
teristics, as well as several clinically relevant mutations
However, none of the above-mentioned resources de-
fine the sub-states of ion channel gating in sufficient de-
tails to capture electrophysiological experiments
performed in this field. In order to address this gap, we
have started to develop a new ontology describing the
biophysical properties of ion channels: the Ion Channel
ElectroPhysiology Ontology (ICEPO). ICEPO focuses on
the biophysical parameters describing the gating proper-
ties of ion channels and more precisely the sequential
transitions between their different gating states. The goal
is to provide a standardized and open ontology that en-
ables the description of voltage-gated ion channel molecu-
lar function and the phenotypic effects of ion channel
Figure 1. Three-state model of voltage-gated ion channels. Closed,
open and inactivated states with the corresponding transitions are
Database, Vol. 2016, Article ID baw017 Page 3 of 7
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Materials and Methods
Development of ICEPO
ICEPO was developed using OBO-Edit. Terms are linked
by the relations ‘is_a’ and ‘part_of’, and is organized as a
simple hierarchy, where each term has a single parent.
The structure of ICEPO is based on (i) the two main
parameters of ion channels during their activity: the con-
ductance and the ion selectivity and (ii) the six possible
molecular transitions through which they can go: activa-
tion, inactivation, recovery, deactivation, reopening and
closed-state inactivation. In addition, each transition
classes are further divided into sub-classes that capture
the two main factors affecting each state: the stimulus and
the time. ICEPO currently contains 48 terms (Figure 2).
The higher level terms of ICEPO are considered children of
the GO concept ion channel activity (GO:0005216), which
makes ICEPO easily interoperable with GO.
The main concepts in ICEPO
The ‘conductance’ of an ion channel is the degree to which
electric current carried by the ions flows through the chan-
nel. We differentiated two types of conductance according
to the methods of ion channel activity recording: the
macroscopic conductance, measured by whole-cell record-
ing, which determines the electric current that flows
through a population of channels in a macropatch; and the
single channel conductance, measured by single channel re-
cording, which determines the electric current that flows
through a single channel in a membrane patch.
The ‘ion selectivity’ is the ability of the channel to be
permeable to a single ion (potassium, sodium, calcium...)
or one type of ion (cation or anion) while excluding the
other. This property depends on the selectivity filter, a re-
gion of the pore of the protein with a specific conformation
adapted to the ion that can flow through it.
The ‘activation’ is the transition from the closed to the
open state. The opening of the channel occurs in response
to a gating signal, allowing the transfer of ions through the
The ‘inactivation’ is the transition from the open to the
inactivated state. Ion channels have an inactivating gate
that closes in the continued presence of the gating signal.
The channel is then in a refractory period. No ion can
pass through the pore and it is unresponsive to stimulus
At least two different inactivation processes have been
described: fast inactivation and slow inactivation, accord-
ing to the time ion channels take to enter and remain in the
inactivated state (17). However, not every voltage-gated
ion channel undergoes both forms of inactivation.
The ‘fast inactivation’ is a rapid type of inactivation
happening typically in few milliseconds at the macroscopic
level. For voltage-gated sodium channels, the fast inactiva-
tion is mediated by a globular region of the protein (so-
called ball-and-chain) that enters the pore from the cyto-
plasmic side and physically prevents ions to pass. This type
of fast inactivation occurs only when the channel is open
and the membrane is still depolarized.
The ‘slow inactivation’ is a deeper inactivation process
activation. For voltage-gated ion channels, it has been
shown that slow inactivation, also known as C-type in-
activation, lasts longer than fast inactivation. This delay
is induced by conformational changes at the selectivity fil-
ter region and the protein requires more time to recover
from it.
The ‘recovery from inactivation’ is the transition from
the inactivated to the closed state in which the channel is
non-conducting. Ion channels can return to this state in ab-
sence of stimulus. For the voltage-gated sodium channels,
this transition requires the repolarization of the membrane
potential in order to shrink the pore and relieve the inacti-
vated gate.
As there are two inactivated states, the fast and
the slow, there are two corresponding terms for recovery:
recovery from fast inactivation and recovery from slow
The ‘deactivation’ is the direct transition from the
open to the closed state. This transition occurs at different
degrees, or not at all, depending on the type of ion chan-
nels. Deactivation rarely happens under physiological con-
ditions for voltage-gated sodium channels that normally
inactivate immediately after opening. However, some
SCN4A variants have been shown to lead to most clinically
severe form of paramyotonia congenita because they im-
pact stronger the deactivation rate constants and induce a
temperature-dependent hyperexcitability of the muscle cell
The ‘reopening’ is the transition from the inactivated to
the open state. This transition results in the so-called resur-
gent sodium current observed in different types of neurons
(19). However, it has also been observed in mutant chan-
nels, which allow the inactivated gate to open before the
pore has gone through the closed state (20).
The ‘closed-state inactivation’ is the transition from the
closed to the inactivated state. This has been extensively
studied for voltage-gated potassium channels, such as
Kv4.1 (KCND1), Kv4.2 (KCND2) and Kv4.3 (KCND3),
which undergo physiologically relevant closed-state inacti-
vation at hyperpolarized membrane potential and less fre-
quent inactivation from open state (21).
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Macroscopic conductance
Single channel conductance
Ion selecvity
Potassium ion selecvity
Sodium ion selecvity
Calcium ion selecvity
Chloride ion selecvity
Smulus dependence of acvaon
Voltage dependence of acvaon
Voltage sensivity of acvaon
Ligand-dose dependence of acvaon
Ligand affinity during acvaon
Membrane-tension dependence of acvaon
Membrane-tension sensivity during acvaon
Time dependence of acvaon
Entry into acvated state
Development of acvaon
Fast inacvaon
Smulus dependence of fast inacvaon
Voltage dependence of fast inacvaon
Voltage sensivity of fast inacvaon
Ligand dose dependence of fast inacvaon
Ligand affinity during fast inacvaon
Membrane-tension dependence of fast inacvaon
Membrane-tension sensivity during fast inacvaon
Time dependence of fast inacvaon
Entry into fast inacvated state
Development of fast inacvaon
Slow inacvaon
Smulus dependence of slow inacvaon
Voltage dependence of slow inacvaon
Voltage sensivity of slow inacvaon
Ligand dose dependence of slow inacvaon
Ligand affinity during slow inacvaon
Time dependence of slow inacvaon
Entry into slow inacvated state
Development of slow inacvaon
Recovery from inacvaon
Recovery from fast inacvaon
Smulus dependence of recovery from fast inacvaon…
Time dependence of recovery from fast inacvaon…
Recovery from slow inacvaon
Smulus dependence of recovery from slow inacvaon…
Time dependence of recovery from slow inacvaon…
Closed-state inacvaon
Figure 2. The ICEPO.
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The gating dependencies in ICEPO
To fully define the mechanism of ion channels transitions,
ICEPO also describes the characteristics of each molecular
transition: the stimulation-dependence (voltage depend-
ence and sensitivity) and the time-dependence (entry into
the state and development of the state).
First, each transition depends on the level of stimula-
tion, referred to as ‘stimulation dependence’. The probabil-
ity of opening of voltage-gated ion channel depends on the
voltage difference across the plasma membrane. For most
voltage-gated ion channels, the greater the depolarization
of the transmembrane voltage, the greater the activation of
the ion channels, reflected by the amplitude of the current
(amount of ions going through the pores). To describe
these properties, electrophysiologists perform steady-state
activation and inactivation analysis to estimate the volt-
age-dependencies of voltage-gated ion channels. For each
transition, we described the concept of ‘stimulus depend-
ence’ and created the corresponding child term for each
transition: voltage-dependence of activation, voltage-
dependence of fast inactivation, voltage-dependence
of slow inactivation, etc. In addition, ion channel activity
depends on its sensitivity to the stimulus. For example, dif-
ferent voltage-gated ion channels have different sensitivity
to voltage. Thus, we created terms to specifically describe
the voltage sensitivity for each transition.
Second, each transition has a specific rate constant
referred to as ‘time dependence’. The time required for the
full activation of voltage-gated ion channels can be meas-
ured through time-to-peak analysis in whole-cell recording
or latency to first opening in single channel recording. We
defined both as the entry into activated state. We defined
also the entry into the (fast or slow) inactivated state re-
flecting the time required for ion channels to be fully inac-
tivated. This parameter is often measured through decay
phase or peak-to-baseline analysis. In addition, the time
during which ion channels stay in a state can be measured.
For example, single channel recording enables to determine
how long an ion channel remains open during a stimula-
tion event, the so-called mean open time. We defined it by
the development of activation. This type of property can
be applied for each transition: development of activation,
development of fast inactivation, development of slow in-
activation, etc.
Annotations using ICEPO
ICEPO enables to accurately annotate each step of voltage-
gated ion channel activity. Using this ontology, we have
started to annotate the family of voltage-gated sodium
channels in human, aiming to capture all effects on the
channels caused by mutations found in patients. We illus-
trate how ICEPO is used for annotation using the SCN5A
(Nav1.5) variant p.Ile141Val. This variant was found in
16 adults from a Finnish family with a history of exercise-
induced polymorphic ventricular arrhythmia (22). When
expressed in the HEK293 cell line, the characterization of
the variant biophysical properties using whole-cell voltage
clamp recording protocol showed that this mutation
shifted the activation curve toward more negative poten-
tials increasing the window current and hastened the kin-
etics of both activation and inactivation. This is captured
using ICEPO as hyperpolarizing the voltage dependence of
activation, as well as hastening the entry into both acti-
vated and inactivated states (Table 1). At the cellular level,
these changes result in a decrease in the excitability thresh-
old of cardiac cells. On the other hand, a number of other
parameters are not affected, including the recovery from
inactivation and the slow inactivation steps.
Capturing the exact molecular details of the defect of
variants will allow to make predictions on possible disease
outcomes for new variants once sufficient data has been
This study presents the first development of ICEPO, an
ontology that describes selected molecular steps of voltage-
gated ion channel function. With minor modifications and
extensions, the ontology could be used to annotate the
electrophysiological parameters of any class of ion chan-
nel. We have started to use ICEPO to annotate the
Table 1. Effects of the SCN5A-p.Ile141Val mutation on the
electrophysiological parameters of the channel
SCN5A-p.lle141 Val Has normal Macroscopic conductance
Hyperpolarizes Voltage dependence
of activation
Has normal Voltage dependence
of fast inactivation
Has normal Voltage sensitivity
of activation
Has normal Voltage sensitivity
of fast inactivation
Hastens Entry into activated state
Hastens Entry into fast inactivated
Has normal Recovery from fast
Has normal Entry into slow inactivated
Has normal Recovery from slow
The relation ‘has normal’ is used to describe results that do not noticeably
differ from wild-type.
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phenotypic effects of voltage-gated sodium channel se-
quence variations. The ontology, as well as our annota-
tions based on the ICEPO will be made available in the
human protein-centric knowledgebase neXtProt (http:// and freely accessible for both scientists
and clinicians. Our main goal is to make use of all pertin-
ent knowledge on the ion channel mutations and on their
biophysical properties to help the prediction of the patho-
genicity of newly discovered genetic variation.
ICEPO is available on the neXtProt ftp site: ftp://ftp.nextprot.
org/pub/current_release/controlled_vocabularies/. Feedback
and suggestions can be sent to
This project is funded by the Swiss National Science Foundation,
Grant Number (CR33I3_156233). The CALIPHO group is funded
by the SIB Swiss Institute of Bioinformatics.
Conflict of interest. None declared.
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... In addition, resting membrane potential, action potential, and refractory period are directly dependent on ion channel behavior. Ion channel gating has its specific and sometimes confusing terminology, like reopening from inactive state, deactivation from open to closed state, and closed-state inactivation (4). It is even difficult for some students to understand the simpler order of opening, inactivation, recovery transitions, and closing states of voltage-gated ion channel (Fig. 2). ...
... (and percentage) of students (n ϭ 159) who responded. A five-level Likert scale rating was used (1)(2)(3)(4)(5). ...
... OBI was chosen as it was developed to describe experimental investigations. Ontologies that were developed to describe computational based neuroscience studies (e.g., [95] and [102]) were less useful to describe this experimental data, as was the Ion Channel Electrophysiology ontology (ICEPO) [115], which described electrical and temporal properties of ion channels. In our case the voltage sensor [116] found within the lateral membrane of outer hair cells is not an ion-channel. ...
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In the past scientists reported summaries of their findings; they did not provide their original data collections. Many stakeholders (e.g., funding agencies) are now requesting that such data be made publicly available. This mandate is being adopted to facilitate further discovery, and to mitigate waste and deficits in the research process. At the same time, the necessary infrastructure for data curation (e.g., repositories) has been evolving. The current target is to make research products FAIR (Findable, Accessible, Interoperable, Reusable), resulting in data that are curated and archived to be both human and machine compatible. However, most scientists have little training in data curation. Specifically, they are ill-equipped to annotate their data collections at a level that facilitates discoverability, aggregation, and broad reuse in a context separate from their creation or sub-field. To circumvent these deficits data architects may collaborate with scientists to transform and curate data. This paper’s example of a data collection describes the electrical properties of outer hair cells isolated from the mammalian cochlea. The data is expressed with a variant of The Ontology for Biomedical Investigations (OBI), mirrored to provide the metadata and nested data architecture used within the Hierarchical Data Format version 5 (HDF5) format. Each digital specimen is displayed in a tree configuration (like directories in a computer) and consists of six main branches based on the ontology classes. The data collections, scripts, and ontological OWL file (OBI based Inner Ear Electrophysiology (OBI_IEE)) are deposited in three repositories. We discuss the impediments to producing such data collections for public use, and the tools and processes required for effective implementation. This work illustrates the impact that small collaborations can have on the curation of our publicly-funded collections, and is particularly salient for fields where data is sparse, throughput is low, and sacrifice of animals is required for discovery.
... The rapid inactivation step enables channel recovery after action potential, and it is facilitated by an intrinsically disordered plug domain. llustration from Hinard et al., 2016. ...
Oxysterol binding protein (OSBP) is a lipid transfer protein that regulates cholesterol distribution in cell membranes. OSBP consists of a pleckstrin homology (PH) domain, two coiled-coils, a “two phenylalanines in acidic tract” (FFAT) motif and a C-terminal lipid binding OSBP-Related Domain (ORD). The PH domain recognizes PI(4)P and small G protein Arf1-GTP at the Golgi, whereas the FFAT motif interacts with the ER-resident protein VAP-A. By binding all these determinants simultaneously, OSBP creates membrane contact sites between ER and Golgi, allowing the counter-transport of cholesterol and PI(4)P by the ORD. OSBP also contains an intrinsically disordered ~80 aa long N-terminal sequence, composed mostly of glycine, proline and alanine. We demonstrate that the presence of disordered N-terminus increases the Stoke’s radius of OSBP truncated proteins and limits their density and saturation level on PI(4)P-containing membrane. The N-terminus also prevents the two PH domains of OSBP dimer to symmetrically tether two PI(4)P-containing (Golgi-like) liposomes, whereas protein lacking the disordered sequence promotes symmetrical liposome aggregation. Similarly, we observe a difference in OSBP membrane distribution on tethered giant unilamellar vesicles (GUVs), based on the presence/absence of N-terminus. Protein with disordered sequence is homogeneously distributed all over the GUV surface, whereas protein without N-terminus tends to accumulate at the interface between two PI(4)P-containing GUVs. This protein accumulation leads to local overcrowding, which is reflected by slow in-plane diffusion. The effect of N-terminus is also manifested in monomeric OSBPderived proteins that tether ER-like and Golgi-like membranes in the presence of VAP-A. Findings from our in vitro experiments are confirmed in living cells, where N-terminus controls the recruitment of OSBP on Golgi membranes, its motility and the on-and-off dynamics during lipid transfer cycles. Most OSBP-related proteins contain low complexity N-terminal sequences, suggesting a general effect.
... Many ontologies exist, including a large number which focus on various aspects of the biological sciences. Of relevance is Ion Channel Electrophysiology ontology, ICEPO [3] that describes concepts that are associated with electrical and temporal characteristics of voltage-gated ion channels. Although some of the concepts (e.g., gating current, ICEPO_0000049) have been used to describe the electrical characteristics of outer hair cells, the membrane protein that forms part of the voltage-sensing component in the lateral membrane of outer hair cells is not an ion-channel. ...
Conference Paper
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Strategies to improve the preservation, searchability, and discoverability of research data are a priority. To facilitate these efforts in cell electrophysiology and biophysics we propose that ontologies be used to design and annotate data, as they provide a substantive metadata structure, with reasoned-definitions arranged in a logical, hierarchal structure where the meaning of data are unambiguously assigned. We illustrate this by describing our cell electrophysiology data with an ontology. We then make this hierarchal structure with definitions the basis of the data architecture which is implemented upon transforming the data into the storage format: Hierarchical Data Format version 5 (HDF5).
... Obtaining a genetic profile for an individual is already a reality thanks to highthroughput genetic testing, 11,34 and efforts are being made to standardize reporting of electrophysiology features of channel variants or medications in order to develop central databases. 35 More complex computer models of mouse and human thalamocortical loops have already been created, 30,36 and more ambitious projects to develop anatomic models of mouse or human brains are underway. 37 This combination of technologies promises to help untangle the mechanisms underlying polygenic epilepsy and lead to novel treatments. ...
Objective: Childhood absence epilepsy (CAE) is a genetic generalized epilepsy syndrome with polygenic inheritance, with genes for γ-aminobutyric acid (GABA) receptors and T-type calcium channels implicated in the disorder. Previous studies of T-type calcium channel electrophysiology have shown genetic changes and medications have multiple effects. The aim of this study was to use an established thalamocortical computer model to determine how T-type calcium channels work in concert with cortical excitability to contribute to pathogenesis and treatment response in CAE. Methods: The model is comprised of cortical pyramidal, cortical inhibitory, thalamocortical relay, and thalamic reticular single-compartment neurons, implemented with Hodgkin-Huxley model ion channels and connected by AMPA, GABAA , and GABAB synapses. Network behavior was simulated for different combinations of T-type calcium channel conductance, inactivation time, steady state activation/inactivation shift, and cortical GABAA conductance. Results: Decreasing cortical GABAA conductance and increasing T-type calcium channel conductance converted spindle to spike and wave oscillations; smaller changes were required if both were changed in concert. In contrast, left shift of steady state voltage activation/inactivation did not lead to spike and wave oscillations, whereas right shift reduced network propensity for oscillations of any type. Significance: These results provide a window into mechanisms underlying polygenic inheritance in CAE, as well as a mechanism for treatment effects and failures mediated by these channels. Although the model is a simplification of the human thalamocortical network, it serves as a useful starting point for predicting the implications of ion channel electrophysiology in polygenic epilepsy such as CAE.
... ICEPO), a specific ontology developed in our group(Hinard et al., 2016),(3)mammalian phenotypes from the Mammalian Phenotype Ontology (Smith & Eppig, 2012), (4) proteins, represented by Gaudet et al. 2017 to describe effects on protein-protein interactions, or (5) protein property, such as protein abundance and stability, represented by an in-house developed protein property vocabulary ( cv_protein_property.obo). ...
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Voltage-gated sodium channels are pore-forming transmembrane proteins that selectively allow sodium ions to flow across the plasma membrane according to the electro-chemical gradient thus mediating the rising phase of action potentials in excitable cells and playing key roles in physiological processes such as neurotransmission, skeletal muscle contraction, heart rhythm and pain sensation. Genetic variations in the nine human genes encoding these channels are known to cause a large range of diseases affecting the nervous and cardiac systems. Understanding the molecular effect of genetic variations is critical for elucidating the pathologic mechanisms of known variations and in predicting the effect of newly discovered ones. To this end, we have created a web-based tool, the Ion Channels Variants Portal which compiles all variants characterized functionally in the human sodium channel genes. This portal describes 672 variants each associated with at least one molecular or clinical phenotypic impact, for a total of 4,658 observations extracted from 264 different research articles. This data was captured as structured annotations using standardized vocabularies and ontologies, such as the Gene Ontology and the Ion Channel ElectroPhysiology Ontology. All this data is available to the scientific community via neXtProt at This article is protected by copyright. All rights reserved
... release/ controlled vocabularies/cv protein property.obo. Finally, for ion channels, the impact on electrophysiological properties is captured with the ICEPO ontology (23). Experimental evidence for each statement is provided, including a reference, an evidence code from the Evidence and Conclusion Ontology (24), and, importantly, a qualitative assessment of the phenotype intensity: mild, moderate or severe. ...
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The neXtProt human protein knowledgebase ( continues to add new content and tools, with a focus on proteomics and genetic variation data. neXtProt now has proteomics data for over 85% of the human proteins, as well as new tools tailored to the proteomics community. Moreover, the neXtProt release 2016-08-25 includes over 8000 phenotypic observations for over 4000 variations in a number of genes involved in hereditary cancers and channelopathies. These changes are presented in the current neXtProt update. All of the neXtProt data are available via our user interface and FTP site. We also provide an API access and a SPARQL endpoint for more technical applications.
Hundreds of human membrane proteins form channels that transport necessary ions and compounds, including drugs and metabolites, yet details of their normal function or how function is altered by genetic variants to cause diseases are often unknown. Without this knowledge, researchers are less equipped to develop approaches to diagnose and treat channelopathies. High-resolution computational approaches such as molecular modeling enable researchers to investigate channelopathy protein function, facilitate detailed hypothesis generation, and produce data that is difficult to gather experimentally. Molecular modeling can be tailored to each physiologic context that a protein may act within, some of which may currently be difficult or impossible to assay experimentally. Because many genomic variants are observed in channelopathy proteins from high-throughput sequencing studies, methods with mechanistic value are needed to interpret their effects. The eminent field of structural bioinformatics integrates techniques from multiple disciplines including molecular modeling, computational chemistry, biophysics, and biochemistry, to develop mechanistic hypotheses and enhance the information available for understanding function. Molecular modeling and simulation access 3D and time-dependent information, not currently predictable from sequence. Thus, molecular modeling is valuable for increasing the resolution with which the natural function of protein channels can be investigated, and for interpreting how genomic variants alter them to produce physiologic changes that manifest as channelopathies. © 2022 American Physiological Society. Compr Physiol 12:3141-3166, 2022.
The epithelial cells of the gastrointestinal (GI) tract communicate with each other and with cells of other organs via a complex network of highly regulated movement of ions and biomolecules. The molecules ensure regulated activity of cells, tissues, and organs of the GI system and the body as whole. The regulated movement and subsequent activities of the biomolecules released from one cell to the target are made possible by receptive substances (receptors) localized on the membrane of the target cells or intracellular organelles, or in the cytosol. This process, which is referred to as cell-to-cell communication or cellular signaling, ensures the regulated functioning of the cells and tissues of the GI system and the whole organism. This chapter is dedicated to the mechanism of cell-to-cell communication and signaling in normal and relates it to how disease develops. Basic mechanisms of GI epithelial cell signaling and gut nutrient receptor sensing (GI chemosensation) are discussed.
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The Gene Ontology (GO; is a community-based bioinformatics resource that supplies information about gene product function using ontologies to represent biological knowledge. Here we describe improvements and expansions to several branches of the ontology, as well as updates that have allowed us to more efficiently disseminate the GO and capture feedback from the research community. The Gene Ontology Consortium (GOC) has expanded areas of the ontology such as cilia-related terms, cell-cycle terms and multicellular organism processes. We have also implemented new tools for generating ontology terms based on a set of logical rules making use of templates, and we have made efforts to increase our use of logical definitions. The GOC has a new and improved web site summarizing new developments and documentation, serving as a portal to GO data. Users can perform GO enrichment analysis, and search the GO for terms, annotations to gene products, and associated metadata across multiple species using the all-new AmiGO 2 browser. We encourage and welcome the input of the research community in all biological areas in our continued effort to improve the Gene Ontology.
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Channelopathies are a heterogeneous group of disorders resulting from the dysfunction of ion channels located in the membranes of all cells and many cellular organelles. These include diseases of the nervous system (e.g., generalized epilepsy with febrile seizures plus, familial hemiplegic migraine, episodic ataxia, and hyperkalemic and hypokalemic periodic paralysis), the cardiovascular system (e.g., long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia), the respiratory system (e.g., cystic fibrosis), the endocrine system (e.g., neonatal diabetes mellitus, familial hyperinsulinemic hypoglycemia, thyrotoxic hypokalemic periodic paralysis, and familial hyperaldosteronism), the urinary system (e.g., Bartter syndrome, nephrogenic diabetes insipidus, autosomal-dominant polycystic kidney disease, and hypomagnesemia with secondary hypocalcemia), and the immune system (e.g., myasthenia gravis, neuromyelitis optica, Isaac syndrome, and anti-NMDA [N-methyl-D-aspartate] receptor encephalitis). The field of channelopathies is expanding rapidly, as is the utility of molecular-genetic and electrophysiological studies. This review provides a brief overview and update of channelopathies, with a focus on recent advances in the pathophysiological mechanisms that may help clinicians better understand, diagnose, and develop treatments for these diseases.
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The aim of this perspective article is to share with the community of ion channel scientists our thoughts and expectations regarding the increasing role that computational tools will play in the future of our field. The opinions and comments detailed here are the result of a 3-day long international exploratory workshop that took place in October 2013 and that was supported by the Swiss National Science Foundation.
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The ability to transmit, organize, and query information digitally has brought with it the challenge of how to best use this power to facilitate scientific inquiry. Today, few information systems are able to provide detailed answers to complex questions about neuroscience that account for multiple spatial scales, and which cross the boundaries of diverse parts of the nervous system such as molecules, cellular parts, cells, circuits, systems and tissues. As a result, investigators still primarily seek answers to their questions in an increasingly densely populated collection of articles in the literature, each of which must be digested individually. If it were easier to search a knowledge base that was structured to answer neuroscience questions, such a system would enable questions to be answered in seconds that would otherwise require hours of literature review. In this article, we describe, a wiki-based website and knowledge management system. Its goal is to bring neurobiological knowledge into a framework that allows neuroscientists to review the concepts of neuroscience, with an emphasis on multiscale descriptions of the parts of nervous systems, aggregate their understanding with that of other scientists, link them to data sources and descriptions of important concepts in neuroscience, and expose parts that are still controversial or missing. To date, the site is tracking ~25,000 unique neuroanatomical parts and concepts in neurobiology spanning experimental techniques, behavioral paradigms, anatomical nomenclature, genes, proteins and molecules. Here we show how the structuring of information about these anatomical parts in the nervous system can be reused to answer multiple neuroscience questions, such as displaying all known GABAergic neurons aggregated in NeuroLex or displaying all brain regions that are known within NeuroLex to send axons into the cerebellar cortex.
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The International Union of Basic and Clinical Pharmacology (IUPHAR) database, IUPHAR-DB ( is an open access, online database providing detailed, expert-driven annotation of the primary literature on human and rodent receptors and other drug targets, together with the substances that act on them. The present release includes information on the products of 646 genes from four major protein classes (G protein-coupled receptors, nuclear hormone receptors, voltage- and ligand-gated ion channels) and ∼3180 bioactive molecules (endogenous ligands, licensed drugs and key pharmacological tools) that interact with them. We have described previously the classification and curation of data for small molecule ligands in the database; in this update we have annotated 366 endogenous peptide ligands with their amino acid sequences, post-translational modifications, links to precursor genes, species differences and relationships with other molecules in the database (e.g. those derived from the same precursor). We have also matched targets with their endogenous ligands (peptides and small molecules), with particular attention paid to identifying bioactive peptide ligands generated by post-translational modification of precursor proteins. Other improvements to the database include enhanced information on the clinical relevance of targets and ligands in the database, more extensive links to other databases and a pilot project for the curation of enzymes as drug targets.
Background: Over the past 15 years, a myriad of mutations in genes encoding cardiac ion channels and ion channel interacting proteins have been linked to a long list of inherited atrial and ventricular arrhythmias. The purpose of this study was to identify the genetic and functional determinants underlying exercise-induced polymorphic ventricular arrhythmia present in a large multigenerational family. Methods and results: A large 4-generation family presenting with exercise-induced polymorphic ventricular arrhythmia, which was followed for 10 years, was clinically characterized. A novel SCN5A mutation was identified via whole exome sequencing and further functionally evaluated by patch-clamp studies using human embryonic kidney 293 cells. Of 37 living family members, a total of 13 individuals demonstrated ≥50 multiformic premature ventricular complexes or ventricular tachycardia upon exercise stress tests when sinus rate exceeded 99±17 beats per minute. Sudden cardiac arrest occurred in 1 individual during follow-up. Exome sequencing identified a novel missense mutation (p.I141V) in a highly conserved region of the SCN5A gene, encoding the Nav1.5 sodium channel protein that cosegregated with the arrhythmia phenotype. The mutation p.I141V shifted the activation curve toward more negative potentials and increased the window current, whereas action potential simulations suggested that it lowered the excitability threshold of cardiac cells. Conclusions: Gain-of-function of Nav1.5 may cause familial forms of exercise-induced polymorphic ventricular arrhythmias.
Resurgent Na current results from a distinctive form of Na channel gating, originally identified in cerebellar Purkinje neurons. In these neurons, the tetrodotoxin-sensitive voltage-gated Na channels responsible for action potential firing have specialized mechanisms that reduce the likelihood that they accumulate in fast inactivated states, thereby shortening refractory periods and permitting rapid, repetitive, and/or burst firing. Under voltage clamp, step depolarizations evoke transient Na currents that rapidly activate and quickly decay, and step repolarizations elicit slower channel reopening, or a “resurgent” current. The generation of resurgent current depends on a factor in the Na channel complex, likely a subunit such as NaVβ4 (Scn4b), which blocks open Na channels at positive voltages, competing with the fast inactivation gate, and unblocks at negative voltages, permitting recovery from open-channel block along with a flow of current. Following its initial discovery, resurgent Na current has been found in nearly twenty types of neurons. Emerging research suggests that resurgent current is preferentially increased in a variety of clinical conditions associated with altered cellular excitability. Here we review the biophysical, molecular, and structural mechanisms of resurgent current and their relation to the normal functions of excitable cells as well as pathophysiology.This article is protected by copyright. All rights reserved
The new and vibrant field of optogenetics was founded by the seminal discovery of channelrhodopsin, the first light-gated cation channel. Despite the innumerous applications that have revolutionized neurophysiology, the functional mechanism is far from understood on the molecular level. An arsenal of biophysical techniques has been established in the last decades of research on microbial rhodopsins. However, application of these techniques is hampered by the duration and the complexity of the photoreaction of channelrhodopsin compared with other microbial rhodopsins. A particular interest in resolving the molecular mechanism lies in the structural changes that lead to channel opening and closure. Here, we review the current structural and mechanistic knowledge that has been accomplished by integrating the static structure provided by X-ray crystallography and electron microscopy with time-resolved spectroscopic and electrophysiological techniques. The dynamical reactions of the chromophore are effectively coupled to structural changes of the protein, as shown by ultrafast spectroscopy. The hierarchical sequence of structural changes in the protein backbone that spans the time range from 10(-12)s to 10(-3)s prepares the channel to open and, consequently, cations can pass. Proton transfer reactions that are associated with channel gating have been resolved. In particular, glutamate 253 and aspartic acid 156 were identified as proton acceptor and donor to the retinal Schiff base. The latter proton transfer is the critical determinant for channel closure. The proton pathway that eventually leads to proton pumping is also discussed. This article is part of a Special Issue entitled: Retinal Proteins - You can teach an old dog new tricks.
Every moment of every day, our skin and its embedded sensory neurons are bombarded with mechanical cues that we experience as pleasant or painful. Knowing the difference between innocuous and noxious mechanical stimuli is critical for survival and relies on the function of mechanoreceptor neurons that vary in their size, shape, and sensitivity. Their function is poorly understood at the molecular level. This review emphasizes the importance of integrating analysis at the molecular and cellular levels and focuses on the discovery of ion channel proteins coexpressed in the mechanoreceptors of worms, flies, and mice.
Opening of stretch-activated ion channels (SACs) is the earliest event occurring in mechanosensory transduction. The molecular identity of mammalian SACs has long remained a mystery. Only very recently, Piezo1 and Piezo2 have been shown to be essential components of distinct SACs and moreover, purified Piezo1 forms cationic channels when reconstituted into artificial bilayers. In line with these findings, dPiezo was demonstrated to act in the Drosophila mechanical nociception pathway. Finally, the 3D structure of the two-pore domain potassium channel (K(2P)), TRAAK [weakly inward rectifying K⁺ channel (TWIK)-related arachidonic acid stimulated K⁺ channel], has recently been solved, providing valuable information about pharmacology, selectivity and gating mechanisms of stretch-activated K⁺ channels (SAKs). These recent findings allow a better understanding of the molecular basis of molecular and cellular mechanotransduction.