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DOI 10.1007/s12013-008-9027-2
REVIEW PAPER
Introduction
As integral membrane proteins, voltage-gated (VG) ion
channels are nestled within a lipid barrier that separates
two aqueous compartments. It has become increasingly
important to consider the function of the plasma membrane
as a dynamic reservoir of lipid signaling molecules. Specific lipid messengers can be enzymatically cleaved from
the plasma membrane upon stimulation by neurotransmitters, neurotrophic factors, and cytokines. Membrane lipid
composition and the availability of diffusible lipids thus
change on the time scale of cellular signaling events.
Combined with long-term changes in membrane composition due to dietary intake, disease, development, or aging,
the short-term availability of lipids such as PIP2, fatty acid
esters of CoA, lysophosphatidic acid (LPA), and free fatty
acids, allows the membrane habitat to be a source of
change in cellular activity.
Voltage-gated ion channels are ideally suited to receive
the messages encoded by lipid molecules. The transmembrane domains of channels are surrounded by the precursors
of lipid signaling and channel gating requires considerable
movement of the protein within this hydrophobic environment. Lipid signals that affect VG ion channel function will
transiently alter the duration and magnitude of the ionic
fluxes across the membrane, providing a direct mechanism
for lipids to regulate excitability, synaptic transmission,
rhythmicity, and contractility. Thus, in neurons and cardiac
muscle, lipid messengers add to the diversity of mechanisms for fine-tuning the electrical properties of the cell. In
this article, we will present and evaluate the evidence for
direct modulation of VG ion channels by polyunsaturated
fatty acids (PUFAs). We have known about this form of ion
channel modulation for at least 16 years now [13] and
there are numerous examples for a variety of VG channels.
60
EET
HETE
diHETE
HDHA
PLA2
Lyso-PAF
DHA
Lyso-PAF
transferase
PAF
PAF acetyl hydrolase
AA
5-LOX
Leukotrienes
PGH2
Other
prostaglandins
TXA2
Lyso-PAF
Ethanolamine
or Choline
Inositol
PLD
AA
IP3
DAG
PA
AEA
AA-Lyso PA
PLA2
COX-2
12-LOX
2-AG
MAG lipase or FAAH
Lyso PA 12-OHPGE2
AEA
EA
glycerol
AA
DAG lipase
61
62
63
64
determine inactivation gating are important in AA modulation [56]. A lack of state-dependence for the AA
modulation also suggested that transitions between inactivated states, rather than open-inactivated transitions may
be sensitive to AA. Overall, these results strengthen the
evidence for a modulation of Ca2? channel inactivation by
PUFAs.
Inhibition of neuronal N-type Ca2? currents by AA has
been well studied at the whole-cell and single-channel level
by Rittenhouse and colleagues. Using cell-attached patches
from rat superior cervical ganglion (SCG) neurons, AA
inhibited N-type current by increasing the probability of
null sweeps which is explained as an increased occupancy
of closed gating states [58]. In related work using the same
cell type, AEA also inhibited the N-type current [59].
There are no studies on PUFA modulation of recombinant
N-type (Cav2.2) channels nor investigation of the impact of
the accessory subunits on this form of channel modulation.
However, important experiments that advance our understanding of native signaling pathways showed that the AAmediated modulation of SCG N-type current required an
M1 muscarinic receptor coupled to the Gq-type of G-protein and both PLC and PLA2 [60, 61].
Polyunsaturated fatty acids inhibit the dihydropyridinesensitive L-type Ca2? channel current studied in neurons
and muscle cells. DHA inhibited the L-type current in
cardiac myocytes [62] and tracheal smooth muscle cells
[63]. PUFAs also inhibited the high-voltage activated Ca2?
current in Muller cells of the retina and a component of this
current may be L-type [64]. In neonatal and adult ventricular myocytes, EPA and other PUFAs reduced plasma
membrane L-type current and elicited a small, but significant, left-ward shift of the steady-state inactivation curve
[65]. Monounsaturated and saturated fatty acids did not
inhibit this current [65]. A rare finding is that PUFAs
increased whole-cell Ca2? current in cardiac myocytes [3].
In this case, however, the pharmacological identity of the
affected current was not known and the structural specificity of fatty acid modulation differed from other studies.
Both long chain unsaturated and, surprisingly, saturated
fatty acids, caused a multifold increase of Ca2? current
amplitude although short-chain fatty acids and fatty acid
esters were not effective [3]. There are no reports on PUFA
modulation of recombinant L-type (Cav1.x) channels nor
tests of the impact of the b, c, and d accessory subunits.
Na? Channels
Evidence for direct effects of PUFAs on VG Na? channel
function is best supported by research done in muscle cells.
There has been limited exploration of PUFA modulation of
neuronal Na? currents. PUFAs inhibited Na? currents
studied in cardiac [6568], skeletal [69], and smooth [70]
65
Inhibition
AA
DHA
HEK 293
HEK 293
HEK 293
TsA201
Cav 3.2
Cav 3.1
AA
AEA
AA
Modulatory agent
[55]
Voltage-dependent inhibition
Inhibition
Inhibition
Abbreviations: PUFA = polyunsaturated fatty acid, AA = arachidonic acid, DHA = docosahexaenoic acid, EPA = eicosapentaenoic acid, ETYA = 5,8,11,14-eicosatetraynoic acid,
AEA = arachidonoylethanolamide (anandamide), SCG = superior cervical ganglion, Alternative channel names: Cav3.1 is a1G, Cav3.2 is a1H, Cav3.3 is a1I
[56]
[57]
[54]
[187]
References
[65]
[62]
[58, 60]
[63]
[59]
Slow inactivation mutants were also tested and had increased affinity for inhibition by AA
Expression system
[53]
[186]
[64]
[3]
[2]
[1]
References
Inhibition
Neonatal rat heart cells and adult rat Variety of PUFAs (Saturated and monounsaturated Inhibition. Left-shifted inactivation curve
ventricular myocytes
fatty acids were not effective)
AEA
DHA and AA
AEA
NG10815 neuroblastoma
AA
NG10815 neuroblastoma
AA
Modulatory agent
Rat osteoblasts
Recombinant T-type
current
current
2?
Cellular preparation
Whole-cell Ca
Whole-cell Ca
2?
66
Cell Biochem Biophys (2008) 52:5984
HEK293t
Examples of modulation of whole-cell and recombinant Na? channel currents. For abbreviations, please see Table 1
DHA, EPA
EPA, DHA
EPA, DHA
HEK293t
AA, DHA
HEK 293
AA
TTX-sensititive and
TTX-resistant
Cardiac muscle
Modulatory agent
Modulatory agent
Expression system
Recombinant
Cellular preparation
Native currents
[71]
[65, 72]
[73]
References
[70]
[65]
[188]
[113]
[66]
[69]
[67, 68]
References
Whole-cell K? current
AA, ETYA
DHA (through peroxidation
products)
AA
IA
IA
Fast-inactivating K?
current
Fast-inactivating K?
current
IA
ITO
Pineal gland
Neocortical neurons
Delayed-rectifier
IK
IK
Sustained K? current
Outwardly rectifying K?
current (predominantly
Kv 1.3 in these cells)
Delayed rectifier
IA
IA
AA
AA
DHA
AA
DHA, AA
AA
AA, ETYA
AA
Pineal gland
AA, DHA
Modulatory agent
IA
Cellular
preparation
Inhibition
Inhibition
Inhibition
Inhibition
Inhibition. Enhanced rate of inactivation. Leftshifted inactivation curve and slowed recovery
from inactivation
Inhibition
[192]
[84]
[191]
[85]
[86]
[81]
[190]
[114]
[80]
[189]
[79]
[78, 116]
[90]
[77]
[87]
[86]
[104]
References
68
Cell Biochem Biophys (2008) 52:5984
LA
AA, ETYA
DHA
Mammalian fibroblasts
Xenopus oocytes
(macropatches)
CHO cells
CHO cells
HEK 293
Xenopus oocytes
CHO cells
Xenopus oocytes
Cellular preparation
Kv 1.2 and Kv
3.1a
Kv 3.4 and Kv
1.1/b1.1
Kv 1.5
Kv 1.5
Kv 1.5 and Kv
2.1
Kv 2.1
Kv 4 (but not Kv
1, Kv 2, nor Kv
3)
Kv 4.3
Kv 4.2
Native Ca2?
activated K?
currents
BK
BK
AA or activation of a Ca2?
dependent PLA2
DHA
Sf9 cells
Kv 1.1
AA (lipoxyenase
activity required)
AA, other fatty acids and other
charged lipids
Modulatory agent
AA
AA, AEA
Modulatory agent
Expression system
Recombinant,
Kv-type
Inhibition
Xenopus oocytes
Kv 7.1 (KCNQ1)
Modulatory agent
Cellular
preparation
K? current or
channel type
Table 3 continued
[76, 197]
[112]
References
[83]
[196]
[82]
[192]
[195]
[194]
[81]
[88]
[191]
[193]
References
[74]
References
1A
100ms
B 125
100
% of control
Abbreviations: IA = Transient or rapidly inactivating, A-type current which may be encoded by the Kv4 gene family plus associated subunits such as KChIPs or other subunits (e.g.,
Kv1.1 ? b1.1); IK = delayed rectifier current which can be encoded by different Kv gene families (but not Kv4); ITO = calcium-independent transient outward potassium current in heart which
is encoded by the Kv4 gene family plus associated subunits; IK1 = intermediate conductance calcium-activated K? channel; BK = big conductance calcium-activated K? channel, also known
as maxiK and slo (Slopoke); ETI = 5,8,11-eicosatriynoic acid (C20:3); LA = linoleic acid (C18:2); ALA = a - linolenic acid (C18:3); OA = oleic acid (C18:1). For additional abbreviations,
please see Table 1
** AA also increased peak current and accelerated activation, but pharmacological evidence suggested this effect was due to PKC activation
Examples of modulation of whole-cell and recombinant K? channel currents. Only channels with voltage-dependent or voltage- and calcium-dependent activation were considered
[43]
Increased current (NPo in single channels). When co-expressed with
b2 or b3 (but not b4) or tested with intracellularly applied free
synthetic b2-ball peptide, the PUFAs also slowed inactivation, but
only when applied from the intracellular side
AA, DHA, OA (Saturated fatty
acids were not effective.)
BK
Xenopus oocytes
[75]
Increased channel activity. Did not require cannabinoid receptors/Gproteins
AEA and methandamide
BK
HEK 293
References
Modulatory agent
Expression system
Table 3 continued
70
75
50
25
0
slow
fast
C normal
reduce Kv4
20 mV
20 ms
71
A Consideration of Mechanisms
While the importance of PUFA modulation of VG channels
has become apparent, an understanding of the molecular
mechanisms remains to be clarified. A schematic overview
of hypothetical mechanisms (Fig. 3) can be used in conjunction with our discussion. First, we will briefly assess
experimental strategies that have been used so far and their
implications.
To determine the direct or indirect nature of channel
modulation by AA, inhibitors of lipoxygenase and cyclooxygenase pathways can establish whether metabolism of
72
protonation of
channel residues
binding
internal
acidosis
oxidation of
channel residues
redox
PUFA
metabolism
oxidative
metabolites
membrane
curvature
membrane
stretch
binding
hydrophobic
mismatch
hydrophobic
interactions with
channel
membrane
compression/expansion
AA is required for the modulation. In addition, commercially available non-metabolizable analogs of AA, such as
ETYA, are useful in assessing whether metabolism of AA
is required for a modulatory effect. When these tools have
been used, the inhibitors generally fail to block AA-mediated effects and ETYA generally mimics the effect of
externally applied AA. Independent assessment that the
inhibitors block the formation of leukotrienes and prostaglandins and allow AA concentrations to remain elevated
during its application to cells has not been reported.
However, in most cases, evidence supports the conclusion
that the modulatory agent is the PUFA itself. Several
exceptions exist [112114]. In rat dorsal root ganglion
neurons, AA application enhanced VG Na? currents and
induced a left-ward shift in the activation curve but these
effects were prevented by a cyclooxgenase inhibitor and
not mimicked by ETYA [113]. Also, in bovine adrenal
chromaffin cells, AA inhibition of BK current was blocked
by inhibitors of lipoxygenases [112].
Since the free cellular concentrations of AA and other
PUFAs are largely unknown, it is difficult to assess the
physiologically relevant concentrations of free fatty acids
in the vicinity of their molecular targets. The range of
130 lM is often effective for experimental modulation of
VG channels and this concentration range includes the
values reported for plasma concentrations of free, unesterified AA (513 lM) [115]. It is important to note, however,
that the local concentration of AA upon cleavage from
excitable membranes is unknown and thus, the relationship
between channel modulation achieved by experimental
application of AA and that achieved by physiologic stimuli
is undetermined. In some preparations, lower concentrations of AA are effective. The most dramatic example is for
IA inhibition by picomolar concentrations of AA applied
Structural Basis
Site-directed mutagenesis is a common approach to test the
functional importance of a specific amino acid residue in
the channel. Variations on this theme include deletion
mutagenesis to remove a group of residues and test for a
loss of a particular function, as well as chimeric swapping
of homologous but non-identical regions of channels and a
test of gain of function in an otherwise insensitive channel
protein. Sometimes, the co-expression of multiple subunits
is tested and results suggest that some channels accessory
subunits may be needed to confer a specific modulatory
effect of PUFAs on VG channels [43, 74, 83]. However,
the application of mutagenesis strategies to explore this
modulation have been limited and the results, so far, are
73
74
Tests of other structural determinants, such as hydrophobic interactions between non-polar regions of the
channel and the hydrocarbon tail of fatty acids would be
useful given the degree to which the channels transmembrane domains interact with lipid [33, 35] and the
hydrophobic interactions of fatty acids and carrier proteins
[123, 124]. Perhaps PUFAs interact with hydrophobic
binding sites within the channel protein, similar to the
effects of local anesthetics [140, 141] or antiarrhythmic
drugs [142] on channels.
75
76
the polar region of the molecule. In a monolayer, the asymmetry of PUFAs induces a negative curvature [20, 152, 161,
162]. Thus, an alternative hypothesis for the structural
mechanism of PUFAs on VG channel function is that a local
increase in PUFAs in one leaflet of the membrane alters
membrane curvature, which impacts the conformational
state of embedded channel proteins. Likewise, lipids that
induce positive curvature would be expected to reverse or
impair the channel modulation by PUFAs.
An impact of PUFAs on membrane curvature may
explain how they activate certain non-VG K2P channels
such as TREK-1 and TREK-2 [159, 163, 164]. In a similar
fashion, an alternative hypothesis for the structural mechanism of PUFAs on VG channel function is that an increase
in PUFAs on one side of the membrane alters membrane
curvature, which impacts the conformational state of
nearby channel proteins. This predicts that the effect of
PUFAs on VG channels would be opposed or reversed by
the application of lysophospholipids to the same side of the
membrane. To our knowledge, such an experiment has not
been reported, although lysophosphatidic acid (LPA) fails
to mimic the effect of AA on inhibition of whole-cell
N-type Ca2? currents [61].
A challenge for an explanation based on membrane
curvature is the ability to explain how the direct application
of AA to cells could induce the same modulatory effect as
upstream activation of PLA2 signaling pathways, a process
that should produce two asymmetric lipids of opposing
conical shapes. One possibility is that one of the products,
such as LPA, is inactive in producing the type or magnitude of change that is necessary for modulation of VG
channels or it cannot access a lipidprotein interaction
region that is required for modulation. Another possibility
is that asymmetric lipids accumulate in both membrane
leaflets, negating an effect on curvature when applied to
only one side of the membrane.
A role for PUFAs on membrane curvature should also
explain how modulation of VG channels is enhanced by
increasing hydrocarbon chain length and increasing number of double bonds in fatty acids. The impact of
asymmetric lipids on membrane bending would predict that
short chain or saturated fatty acids would have a smaller
effect on monolayer curvature and assume a more symmetric shape within a lipid bilayer. The concept of
membrane bending is difficult to assess because one would
like a direct measure of the membrane curvature and not
indirect measures, but the hypotheses have sound experimental predictions, based on our knowledge of the effects
of lipids on membrane geometry.
These explanations for the modulation of VG channels
by PUFAs are not mutually exclusive, nor do they detract
from the physiologic importance of PUFA modulation of
cellular excitability. Furthermore, specificity of action may
77
78
Conclusions
The studies reviewed here support a role for direct PUFA
modulation of the function of several structurally related
but distinct ion channels in excitable cells. Important
advances have been made in understanding the lipid nature
of the plasma membrane and the source of different lipid
messengers. In several instances, we have a comprehensive
understanding of the physiologic impact of the PUFA
modulation of certain VG channels. In addition, the
numerous examples of native and recombinant VG channels that are affected by PUFAs includes insights on the
structural characteristics of fatty acids, a requirement for b
subunit co-association in certain cases, and the relationship
between PUFAs and channel inactivation. However, an
understanding of the structural basis for this modulation
remains elusive. We have reviewed experimental strategies
used to assess the mechanisms of PUFA modulation to date
and discussed recent results from mutagenesis studies
designed to assess a molecular site of action. A restlessness
with the current evidence suggests that we consider alternative explanations, including the mechanical forces that
alter lipidprotein interactions. We have reviewed critical
elements of this research and identified future experimental
strategies to fill the gaps in our understanding of the
mechanisms of PUFA modulation of VG channels.
Several additional questions remain unanswered. We do
not know the lifetime of AA as a signaling molecule following physiologic stimulation of its cleavage from
membrane phospholipids. Since AA is metabolized to
leukotrienes, prostaglandins, and thromboxanes (Fig. 1), its
lifetime may be short, and its duration of availability is
79
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
Acknowledgment The authors thank the Thomas and Kate Jeffress
Foundation and the Arts and Sciences Deans Office for research
support.
18.
19.
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