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(Received for publication, August
21, 1995; and in revised form, October 26, 1995) From the
Amylin is a 37-amino acid cytotoxic constituent of amyloid
deposits found in the islets of Langerhans of patients with type II
diabetes. Extracellular accumulation of this peptide results in damage
to insulin-producing
Amylin is a peptide hormone co-secreted with insulin from the
In addition to
humans, only a few other mammals, such as primates (13) and
cats (14) are known to form amyloid deposits and develop type
II diabetes. Rats are among the organisms that do not form amyloid and
do not develop type II diabetes(15, 16) . It has been
shown in vitro that amyloidogenic human amylin is more toxic
than nonamyloidogenic rat amylin(9) . Amylin has been shown
to interact with phosphatidylcholine liposomes resulting in drastic
changes in its secondary structure. The peptide was transformed from a
combination of Based on the above evidence, we supposed that
the mechanism of amylin toxicity might be an increase in
Human amylin peptide at concentrations ranging from 1 to 10
µM dramatically increased the conductance of pure planar
lipid bilayer membranes (Fig. 1). At identical concentrations,
nonamyloidogenic and noncytotoxic rat amylin produced no change in
membrane conductance.
Figure 1:
Induction of ionic currents in a planar
lipid bilayer membrane by human amylin. Membrane current is shown as a
function of time. The current through an unmodified lipid bilayer
membrane is very low and is indistinguishable from zero in this figure.
Addition of 6 µM rat amylin (first arrow) to the
aqueous phase resulted in no detectable change in the membrane current,
whereas the same concentration of human amylin (second arrow)
dramatically increased the membrane current. The black lipid membrane
was composed of soybean phospholipids (azolectin). Aqueous salt
solutions contained 100 mM KCl, 5 mM Tris-HCl, pH
7.5. Membrane potential was initiated at + 50 mV, to test
stability, and then switched to -50 mV for the rest of the
experiment.
The amylin-induced conductance showed
steady-state voltage-dependent behavior (Fig. 2). At negative
voltages, the conductance remained stable. At positive voltages, it
turned off during the first 3-5 min after a stepwise increase in
voltage from 0 to values greater than +10-20 mV. The
percentage of decrease in conductance was dependent on the amplitude of
applied positive voltage. At +60-70 mV, membrane conductance
decreased to 20-30% of its initial level. Although greater
increases in the voltage applied result in greater decreases in
membrane conductance, a complete conductance turn off has never been
observed. This voltage-dependent inactivation of membrane current was
reversible.
Figure 2:
Voltage dependence of amylin-induced
membrane conductance is asymmetric. Inset, voltage-dependent
inactivation of amylin-induced membrane current in response to a
voltage step from 0 to +50 mV. At zero time, the current through
the membrane is maximal and is not inactivated. 3-5 min after the
voltage step, approximately 70% of the original conductance is
inactivated, and the membrane current is stabilized. On the graph, data
of the relative steady-state conductances were obtained as the ratio of
the steady-state currents to the initial maximum currents from the
recordings as shown in the inset. Conditions were as in Fig. 1.
Amylin was also able to insert into membranes at
positive voltages (Fig. 3). When human amylin was added to the
membrane at +50 mV, the current increased to a plateau in
approximately 5 min. This steady-state current was increased
3-5-fold by reversing the voltage polarity (-50 mV).
Switching back to positive voltage (+50 mV) effectively reduced
the membrane current close to its previous level. If the voltage
polarity is again reversed (-50 mV), the channels fail to reopen
immediately, but they reopen over several minutes (data not shown).
Figure 3:
Membrane insertion of amylin channels at
``inactivating'' voltages. Human amylin peptide was added at
concentration of 5 µM to the cis-side of the
membrane, which was held at +50 mV (an ``inactivating
voltage''). After stady-state current was achieved, membrane
potential was switched to zero and then to -50 mV. This reversal
of the sign of the membrane potential resulted in a fast increase in
membrane current (channel ``opening''). Returning to the
original membrane holding potential (+50 mV) turned off the
current to approximately its original level. A membrane with a diameter
of 500 µm was made of a 15 mg/ml solution of
phosphatidylcholine/phosphatidylserine/phosphatidic acid, 3:1:1 in
heptane. Salt solutions contained 10 mM KCl, 5 mM Tris-HCl, pH 7.5.
Extensive washing out of the amylin-containing aqueous phase with
amylin-free aqueous solution of the same salt composition (20 volumes)
did not reduce or eliminate the amylin-induced conductance (data not
shown), suggesting that association of amylin with the membrane is
irreversible. The conductance induced by human amylin is due to the
formation of ion-permeable channels (Fig. 4A). These
channels exhibited a single channel conductance of approximately
7-8 picosiemens in 10 mM KCl (Fig. 4B).
The single channel current jumps were quite uniform in size. At least
four distinct levels can be discerned in this tracing. The conductance
of the open state channel was ohmic (Fig. 4C). This
suggests that the voltage dependence observed in macroscopic currents
reflects a voltage-dependent probability of channel inactivation rather
than a change in single channel conductance as a function of voltage.
Although amylin clearly induces voltage-dependent conductance in 100
mM KCl, clean single channel recordings were difficult to
obtain in this solution, possibly due to the very rapid rate of channel
opening and closing in 100 mM KCl, or to the tendency of
amylin to aggregate rapidly in higher salt.
Figure 4:
Single channel currents induced by human
amylin. A, current trace is shown as membrane was held at
-70 mV, to which human amylin had been added to a final
concentration of 3 µM. Note the uniformity of single
channel current size. The solvent-containing membrane was composed of
soybean phospholipids (azolectin). Aqueous salt solutions contained 10
mM KCl, 3 mM Tris-HCl, pH 7.4. B, a
histogram of single channel conductance sizes. Data are taken from the
membrane depicted in A. ``Events'' were counted by
observing the initial insertion into the membrane of channels, and thus
each of the observations represents an independent channel event and
not merely opening and closing of the same channel. C, the
current-voltage relationship for the open state of the channel is
linear.
The ionic selectivity of
amylin channels was relatively poor. The channels exhibited a reversal
potential of 14 mV (cation selective) in an 8-fold gradient of NaCl.
Other selectivity experiments indicated that the channel is permeable
to Na The dependence of membrane conductance on the
concentration of amylin in the aqueous solution was linear (Fig. 5). This dependence suggests that a monomer or an amylin
polymer, preexisting in the aqueous phase, interacts with the membrane
and forms the channel.
Figure 5:
Membrane conductance as a function of
amylin concentration. Data are plotted from numerous experiments,
indicating that the amylin-induced conductance is directly proportional
to the concentration of human amylin peptide in the aqueous phase
surrounding the membrane. Each point on the graph corresponds to the
average measurements from three experiments. Membranes with a diameter
of 500 µm were made from azolectin. Aqueous solutions contained 100
mM KCl, 10 mM Tris-HCl, pH
7.5.
Amylin increased the lipid bilayer
conductance in potassium chloride or sodium chloride at salt
concentrations ranging from 10 mM to 1 M and at pH
values ranging from 4.0 to 9.0. Whereas amylin channel-forming activity
(number of channels incorporated into the membrane at a given peptide
concentration and time) was not dependent on pH, it was dependent on
salt concentrations. Higher salt concentrations caused a decrease in
channel-forming activity. As shown in Fig. 6A, the
channel-forming activity of amylin in salt solutions composed of 10
mM KCl was more than 100 times higher than that in 1 M KCl.
Figure 6:
Dependence of amylin channel forming
activity on ionic strength and lipid composition. A, membranes
were composed of azolectin, and salt concentration was varied. B, measurements were carried out in constant salt solutions
containing 10 mM KCl, 3 mM Tris-HCl, pH 7.5; lipid
composition of membranes were varied as shown. The solid bars correspond to the mean of three to five measurements. Error
bars show the standard deviation. Painted membranes with a
diameter of 500 µm were used in all experiments. Channel forming
activity of amylin was calculated as the number of channels
incorporated into the membrane during 10 min following peptide addition
to a final concentration of 5
µM.
Lipid composition of bilayer membrane was also found to
play a role in the channel-forming activity of the peptide (Fig. 6B). Amylin exhibited the highest activity in
membranes composed of a mixture of
phosphatidylcholine/phosphatidylserine/phosphatidic acid, 3:1:1
(w/w/w). These membranes contained approximately 40% negatively charged
lipids and therefore carried a high net negative surface charge. Thus,
these membranes were approximately 6 times more sensitive to amylin
than membranes of pure soybean phospholipids (azolectin), which are
composed of approximately 20% negatively charged lipids. Membranes
composed of azolectin with cholesterol (cholesterol makes membranes
more rigid) as well as those composed of diphytanoylphosphocholine
(lipid head group net charge is zero) were only slightly sensitive to
amylin. In experiments directed toward possible modulators of amylin
membrane activity, compounds related to Type II diabetes such as
glucose (30 mM), tolbutamide, chlorpropamide, and
glybenzcyclamide (2 mM) were studied. No modulation of amylin
channel-forming activity nor change in amylin-induced ion currents was
found after exposure to these compounds. Our results demonstrate that human amylin interacts with
membranes and is capable of ionic channel formation in lipid bilayers.
The highly homologous rat amylin, which differs from human amylin at
only 6 amino acid residues, did not form channels in planar lipid
bilayers at comparable concentrations, indicating that it is unlikely
that proteins of this general length and sequence form channels. The
concentrations of human amylin used to obtain channel activity are
quite comparable with the concentrations of other cytotoxic peptides,
such as defensins (19) , A The
total net charge of human amylin peptide is +5. Therefore it is
not surprising that amylin had a higher channel forming activity on
bilayers composed of negatively charged phospholipids and that
increasing net lipid surface charge from 20 to 40% caused a significant
increase in activity. Decreased channel formation at high salt
concentrations can be explained by the screening of the membrane
surface negative charge at high ionic strength solutions. The
voltage dependence of amylin induced ion currents is consistent with
the fact that amylin has a net positive charge. In this case, the
opposite negative voltage can help ``drive'' amylin across
the membrane, transforming amylin into the ion conducting transmembrane
conformation. However, since channels can insert into the membrane in a
``closed'' (low conductance) state at ``closed''
voltages (Fig. 3), the insertion process must be driven by
nonelectrostatic forces. Several lines of evidence suggest that
channel formation may explain the cytotoxicity of amylin. 1) Channel
formation occurs at concentrations comparable with those required for
cytotoxicity(9) . 2) The relatively poor selectivity of amylin
channels would tend to lead to disruptions of ionic homeostasis,
including influxes of Ca We did not
observe the requirement of actual contact between the membrane and
amylin fibrils that was reported by Lorenzo et
al.(9) . This may reflect a requirement in the cellular
system for a very large membrane leak in order to obtain cytotoxicity,
due to the fact that Whole cell patch clamp recording from Several cytotoxic, amyloid- forming peptides have now been
demonstrated to form ion-permeable
channels(20, 21, 33, 34) . While
this may be coincidental, a more interesting view is that the
structural properties of peptides that form
Volume 271,
Number 4,
Issue of January 26, 1996 pp. 1988-1992
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
cell membranes and cell death. We report
here that at cytotoxic concentrations, amylin forms voltage-dependent,
relatively nonselective, ion-permeable channels in planar phospholipid
bilayer membranes. Channel formation is dependent upon lipid membrane
composition, ionic strength, and membrane potential. At 1-10
µM, cytotoxic human amylin dramatically increases the
conductance of lipid bilayer membranes, while noncytotoxic rat amylin
does not. We suggest that channel formation may be the mechanism of
cytotoxicity of human amylin.
cells of the islets of Langerhans in the
pancreas(1, 2, 3) . It is postulated that
amylin has a regulatory function that opposes the action of
insulin(4, 5) . The pathology of non-insulin-dependent
(type II) diabetes mellitus is characterized by an extracellular
accumulation of fibrillar amyloid, which consists largely of
amylin(6, 7, 8) . The amount of amylin
deposited is proportional to the insulin requirements of the patient
and thus to the clinical severity of the disease(6) . It has
recently been reported that human amylin is toxic to islet
cells(9) . Although it is not clear why amylin forms amyloid
deposits, the mechanism of amylin cytotoxicity is believed to be the
interaction of amyloid with cell
membranes(10, 11, 12) .
-helical and -sheet structures to a largely
-sheet structure(17) . The structure of noncytotoxic rat
amylin, which is mainly disordered in aqueous solution, was not
affected by liposomes. cell
membrane permeability to ions. We therefore investigated the
interaction of amylin with planar lipid bilayer membranes.
Materials
Human amylin (HPLC (
)grade,
>99% purity) was purchased from Bachem California, Torrance, CA, and
rat amylin (HPLC grade, >98% purity) was from Bachem Biosciences,
King of Prussia, PA.
1,2-Diphytanoyl-sn-glycero-3-phosphocholine, L--phosphatidylcholine (plant), L--phosphatidylserine (brain, sodium salt),
azolectin (soybean phosphatide extract, granulated, 45% phosphocholine
content), and 1,2-dimyristoyl-sn-glycero-3-phosphatidic acid
were purchased form Avanti Polar Lipids, Inc., Birmingham, AL.
Tolbutamide and chlorpropamide were from Sigma, and glybenzcyclamide
was from Aldrich. Lyophilized amylin was dissolved in deionized water
at a concentration of 2 mg/ml, distributed into 25-µl aliquots, and
stored at -20 °C. The peptide was thawed before addition to
the lipid bilayer membranes and never frozen again.Planar Lipid Membrane Experiments
Planar lipid
bilayer membranes were formed as described previously (18) from
15 mg/ml solution of lipids in n-heptane at the end of Teflon
tubing 250 or 500 µm in diameter. The construction of the chamber
allowed substitution of the solution in one compartment (cis,
to which peptides were added) within several seconds. After the
membrane had turned black, the solution in the cis-side was
replaced with amylin-containing solution. Usually, after the initial
incorporation of amylin, free peptide in the aqueous solution was
washed out. Membranes used in experiments were stable and had
conductances of less than 10 picosiemens up to voltages of ± 100
mV for a period of at least 10 min prior to amylin addition.Recording Equipment
Voltage clamp conditions were
employed, and contact with the aqueous phases was made using Ag/AgCl
electrodes with agar salt bridges. Electrode asymmetry was always less
than 1 mV. Membrane formation was verified by monitoring membrane
capacitance and resistance. Data were digitized and stored on VHS tape
and played back for later analysis. An Axopatch 1C amplifier with
headstage CV-3B was used for measuring membrane current. For data
acquisition, a digital tape recorder and video cassette recorder
allowed recording of large amounts of data. A storage oscilloscope was
used for monitoring membrane capacitance and single-channel recordings.
The cis-solution was taken as the virtual ground and the sign
of the membrane voltage corresponded to the trans side of the
membrane.
, K
, Ca
, and
Cl
.
(20) , A
25-35(21) , magainins(22) ,
cecropins(23) , and sarcotoxins(24) , needed to form
channels in bilayer membranes. The facts that amylin channels can form
in different lipid mixtures, are quite stable, are irreversibly
associated with the membrane, and are all uniform in size argue
strongly that they are not the result of nonspecific membrane
disruption or peptide-induced defects in bilayer structure. and Na
and
effluxes of K
and other vital cellular constituents.
Prolonged elevations of intracellular Ca
levels, for
example, may lead to cellular damage and even death
(apoptosis)(25, 26) . In addition to the potentially
serious effects of these ionic changes, the cell would face increased
energy demands as various pumps and exchangers attempted to compensate
for these ionic disturbances. 3) Amylin channels exhibit voltage
dependence, which would tend to keep channels in the open state at
typical cellular transmembrane voltages. 4) The fact that human amylin
forms channels and rat amylin does not is highly suggestive, since
human amylin is toxic and amyloidogenic and rat amylin possesses
neither property(9) . 5) Amylin not only kills
cells but
is able to kill other cell types. This relative nonspecificity is
reflected in the fact that amylin can form channels in a planar lipid
bilayer lacking any proteinaceous receptor. 6) It has been shown that
human amylin interacts with phosphatidylcholine membranes and adopts
-structure (17) . In contrast with human amylin, rat
amylin did not change conformation upon addition to phosphatidylcholine
membranes. The -pleated sheet structure adopted by human amylin
upon interaction with membranes is consistent with the -structure
found in the neurotoxic and channel-forming peptide A25-35 (27) and is consistent with the -structure seen in the
bacterial porin (28) and mitochondrial outer membrane channel
VDAC(29) . (7) The amount of amyloid found in
pancreatic islets is proportional to the amount of cell
destruction and to the insulin requirements of the
patient(6, 30) . Thus increased amylin deposition may
lead to increased channel formation and cell destruction, thereby
increasing the insulin requirement of the patient. cells do not have a very tight membrane
(membrane resistance, 10
ohms(31) ). Since the
channels we have observed have a conductance of 7.5 picosiemens in 10
mM KCl, it would take approximately 100 channels to make a
significant (doubling the conductance) leak in these membranes
(assuming a single channel conductance of approximately 100 picosiemens
in physiologic solution). Thus, it may be that islet cell dysfunction
and destruction in vivo is a very slow, gradual process that
builds up over considerable lengths of time. Blockers and inhibitors of
channel activity may have potential therapeutic value in type II
diabetes. cells has
demonstrated that the addition of amylin induces hyperpolarization of
the cell membrane and increases membrane current(32) . Our
present results predict a depolarizing effect on cells. Since the
patch clamp results were obtained at lower amylin concentratious
(1-500 nM), they may represent a specific amylin
interaction with an ion channel already present in the cell
membrane.-sheet and aggregate
into fibrils suit these peptides for membrane insertion and channel
formation.
)
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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