AMER. ZOOL., 38:280-290 (1998)
Membrane Lipids: What Membrane Physical Properties are Conserved
during Physiochemically-Induced Membrane Restructuring?1
E. EUGENE WILLIAMS 2
Department of Biology Indiana University/Purdue University at Indianapolis,
Indianapolis, Indiana 46202.
SYNOPSIS. Current theories assert that organisms finely adjust the order, or fluidity, of their cellular membranes in response to changes in their physiochemical
environment (e.g., pressure, temperature, salinity, etc.). However, membrane order
may not be the only property that is conserved. The most commonly observed
alterations in cell membrane composition under conditions of altered physiochemical environment, namely changes in the phosphatidylethanolamine/phosphatidylcholine (PE/PC) ratio and the content of highly unsaturated acyl chains, are difficult to fully reconcile with the conservation of membrane order alone. This report
reviews the literature concerning two properties of membranes that may play vital
roles in the adaptation of cellular membranes to changing environments: a) the
tendency of membranes to relax into the reversed hexagonal phase and b) the
occurrence and structure of lipid-driven domains within the membrane. The tendency of a membrane to form the reversed hexagonal phase is a property central
to a variety of important cellular events. This tendency is tightly regulated by
variation of the ratio of hexagonal phase-forming lipids to lamellar phase-forming
lipids in the membrane. In most animal cells, this corresponds to the PE/PC ratio.
Highly unsaturated acyl chains, in conjunction with cholesterol, modulate the occurrence and structure of lipid-driven membrane domains. These membrane domains are also critically involved in a number of key cellular processes. The
changes in membrane lipid composition that occur during adaptation to the environment may be required for the preservation of the tendency to form nonlamellar phases and of the occurrence and specific structure of domains within the
membrane, in addition to overall membrane order.
INTRODUCTION
Biological membranes are assemblies of
lipid and protein that separate inside from
outside and are responsible for the distinction between compartment and environment. Membranes are involved in a variety
of indispensable cellular functions. They
provide a means of retaining and controlting resources by forming a barrier to diffusion. This barrier function forms the basis
for the establishment, maintenance, and
regulated utilization of transmembrane solute gradients for use in acquiring metabolic
substrates and for energy production. Membranes are responsible for the selected bulk
1
From the Symposium The Biology of Lipids: integration of Structure and Function presented at the
uptake and release of material into and out
" a n d exocytosis and for
t h e ex
tensive network of vesicular traffickin
8 between organelles. They possess the
molecular machinery necessary for transmembrane signal transduction and store the
P° o 1 o f Precursors used to form hpid-den v e d second
messengers. Without exception
- t h e s e activities depend on, and are inrluenced by, the physical milieu provided
by the molecules making up the membrane
^P' d bilayer.
Cellular membranes are complex molecu l a r ma s
that
y
^ h e l d together by relativel
y w e a k forces. Membranes of higher
organisms are composed of hundreds of different proteins and lipids. The lipid matrix
of the bilayer is held together not by strong,
covalent bonds, but instead by Weaker Seco f the cel1 via endo
CZ^TZ^IST^LT^TA^-
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querque. New Mexico.
2
E-mail: ewiiiiam®indyunix.iupui.edu
and hydrophobic interactions). Thus m e m branes are dynamic structures; individual
280
LIPIDS AND MEMBRANE PHYSICAL PROPERTIES
281
reversed hexagonal
phase
AAAAAAAA
W W VVVY
decreased order
liquid crystalline
phase
increased order
gel phase
FIG. 1. Changes in the physical or chemical environment can alter the phase state of biological membranes.
Changes in temperature and pressure are shown as examples. Other physiochemical factors which can have the
same effects include pH, salinity, ion content, and hydration state. Under normal conditions the membrane exists
in the lamellar liquid crystalline phase. The reversed hexagonal and gel phases are incapable of sustaining
normal cell function and are avoided.
membrane components are free to spin,
wobble, and diffuse laterally within the
membrane leaflet. The lack of rigid connections between molecules and the dynamic
organization of the membrane are essential
for its proper functioning (Singer and Nicolson, 1972). Yet these very features also
make biological membranes exceptionally
sensitive to changes in the physical and
chemical environment (e.g., temperature,
pressure, pH, salinity, ionic strength, hydration state, etc.).
Even modest changes in these environmental physiochemical factors have a direct
and powerful influence on the molecular
milieu of the membrane that in turn can
have serious effects on membrane function.
Under normal conditions, cellular membranes exist in the lamellar, liquid crystalline phase (Fig. 1). In this state the membrane is fully functional. In simple terms,
as environmental conditions change, the
molecular organization of the membrane
becomes more (less) ordered, rates of molecular motion are reduced (increased) and
the phospholipid acyl chains become more
(less) tightly packed (Fig. 1). At one end of
this spectrum, corresponding to conditions
such as, for instance, low temperature or
high pressure, the membrane passes from
the liquid crystalline phase into the gel
phase. Lipids in the gel phase are highly
ordered (Fig. 1) and the membrane is generally non-functional. Membrane function
can be dramatically impaired well before
the liquid crystalline-gel phase transition
point is reached. At the other end of the
spectrum, corresponding to conditions such
as increased temperature or reduced pressure, membrane order is steadily decreased.
The membrane can undergo another phase
transition, in this case to the reversed hexagonal phase. The reversed hexagonal
phase is a non-lamellar phase characterized
by extended cylinders of phospholipid with
the acyl chains extending away from the
center of the cylinder, into which the phospholipid polar head groups are packed (Fig.
1). The liquid crystalline to hexagonal
phase transition destroys the barrier properties of the membrane and the cell is unable to survive. Again, substantial loss of
function can occur well before the transition is reached. Thus, for any given membrane there is a relatively narrow range of
physiochemical conditions that can be tolerated.
Organisms can be found living under
conditions that far exceed the range tolerated by most individuals. Yet given time,
282
E. EUGENE WILLIAMS
individuals can adjust (adapt, acclimate, acclimatize) to new environmental conditions.
One mechanism responsible for this is the
ability of cells to counter deleterious physiochemical effects by altering the lipid
composition of their membranes (Hazel and
Williams, 1990). Structurally, membrane
lipids (mostly phospholipids) are extremely
diverse, and each structure is characterized
by a unique set of physical properties. Lipids with physical properties suited for the
prevailing environment are chosen for incorporation into the newly restructured
membrane. By making the appropriate metabolic adjustments, membrane lipids are refashioned so that the deleterious effects of
the novel environment are countered and
the lamellar liquid crystalline phase is
maintained.
The preservation of the liquid crystalline
phase in the face of altered environmental
conditions appears to be an essential requirement for the cells of all organisms.
The conservation of membrane phase state
has been termed homeophasic adaptation
(McElhaney, 1984a, b). A related concept,
homeoviscous adaptation (Sinensky, 1974),
holds that cells regulate membrane order
(or fluidity) at a finer level, and maintain it
close to some specific value. Both theories
stress that a change in membrane composition is required to conserve an important
physical property of the membrane. Homeoviscous adaptation is the most cited of
the two theories, and has been the subject
of recent reviews (Cossins, 1994; Hazel,
1995). Based on the combined literature,
homeoviscous and homeophasic adaptation
play major roles in the restructuring of cell
membranes when organisms are faced with
a thermal challenge. These models of membrane structure have proven to be very useful, but they nevertheless fail to fully explain the two most widely observed, and
perhaps most fundamental, differences
found in membranes from thermally acclimated species. Specifically, membranes
from organisms exposed to cold have 1) elevated ratios of phosphatidylethanolamine
to phosphatidylcholine (PE/PC) and 2) increased levels of polyunsaturated acyl
chains among the phospholipids (Hazel and
Williams, 1990). These alterations in mem-
brane lipid composition are not altogether
consistent with the regulation of membrane
order (Lee, 1991; Hazel, 1995). For example, because molecules of PE can form intermolecular hydrogen bonds (Sen et al.,
1988), elevated levels of PE are expected
to increase, not decrease, membrane order.
Also, monoenes and dienes (acyl chains
with one and two double bonds, respectively) are far more effective at altering membrane order than are polyunsaturates (Holte
et al., 1995). Thus, although membrane order is an important physical property that is
preserved during acclimation to novel environments, it is apparently not the only
one. Other properties of the lipid matrix of
the membrane also seem to be maintained.
It is possible that the modulation of these
other properties during environmental physiochemical challenge is equally as important as the maintenance of membrane order
for the preservation of cell function. The
nature of these other physical properties
might be illuminated by answering the
question of what properties of membrane
organization other than order are influenced
by the observed compositional changes?
Two possibilities are presented below.
THE TENDENCY TO FORM THE REVERSED
HEXAGONAL PHASE
Some phospholipids, in isolation, spontaneously form the reversed hexagonal
phase (Fig. 1) under normal physiological
conditions. When exposed to excess water,
most membrane phospholipids form the lamellar liquid crystalline phase. Phosphatidylcholine (PC), the most abundant phospholipid in animal cell membranes, is such
a lipid. However other membrane phospholipids, including the second most abundant
animal cell phospholipid, phosphatidylethanolamine (PE), spontaneously form nonlamellar structures like the reversed hexagonal phase (Harlos and Eibl, 1981). The
cone-shaped geometry of the latter lipids,
with their relatively small head group size
coupled with the relatively large area occupied by the acyl chains (Fig. 2), promotes
the formation of these structures (Israelachvili et al, 1980; Gruner, 1985). As noted,
non-lamellar phases are inconsistent with
normal membrane functioning. Why then,
LIPIDS AND MEMBRANE PHYSICAL PROPERTIES
v h /l c a(,=
shape
phase
example
<0.5
0.5-1.0
PC
PE
FIG. 2. The molecular shape of membrane lipids. The
shape parameter, vh/lcao, where vh represents the volume of the hydrophobic region, lc the critical acyl
chain length, and ao the optimal surface area (Israelachvili et al., 1980), determines their preferred phase
state. Cone-shaped lipids, like lysophospholipids
(lysoPL, i.e., phospholipids containing a single acyl
chain), prefer to form spherical micelles. Lipids with
an overall cylindrical shape, like PC, tend to form lamellar bilayers, and lipids with the shape of an inverted cone, like PE, tend to form the reversed hexagonal phase.
do cells contain large proportions of an apparently pernicious phospholipid?
The incorporation of hexagonal phaseforming lipids like PE into a membrane
composed of otherwise lamellar phaseforming lipids causes a strain to develop
within the membrane as the non-lamellar
species attempt to relax into the hexagonal
phase (Gruner, 1985). This curvature stress,
or the tendency of the bilayer to form the
hexagonal phase, is restrained by the presence of the other lipids in the membrane
and by the thermodynamic constraint of the
membrane leaflets being unable to separate
from one another (Gruner, 1985). Such a
membrane has a propensity to form the hexagonal phase that is not realized under normal conditions. The constraints can be
overcome, and the hexagonal phase can actually form, when environmental parameters reach threshold levels, for example, at
a particular temperature, pH, or hydration
state. Thus a low lamellar to hexagonal
phase transition temperature is an indication
of a high tendency to form the hexagonal
phase. Because all membranes studied to
date contain significant quantities of hexagonal phase-forming lipids, this propensity
283
to form the hexagonal phase appears to be
a universal property of cell membranes.
The importance of the tendency of cell
membranes to revert to the hexagonal phase
is revealed by the fact that it is tightly regulated (Lindblom and Rilfors, 1989; Osterberg et al, 1995; Morein et al, 1996).
When confronted with a change in the
physical environment, cells carefully balance the content of lamellar phase-forming
and hexagonal phase-forming lipids in their
membranes (Lindblom et al, 1993; Rilfors
et al, 1994). Under a variety of culture
temperatures, membranes of E. coli are
poised identically with respect to their tendency to form the hexagonal phase. In all
cases the lamellar to hexagonal phase transition temperature of lipid extracts is 18°C
above the growth temperature (Morein et al,
1996). Mutant strains that are unable to produce PE instead produce diphosphatidylglycerol. The mutant cells have a requirement
for high concentrations of Mg2+ (Rietveld
et al, 1993, 1994). At high Mg2+ concentrations diphosphatidylglycerol forms the
hexagonal phase (De Kruijff et al, 1982).
In microorganisms that naturally lack PE,
hexagonal phase-forming glycolipids (monogalactosyldigylceride or monoglucosyldiglyceride) are substituted and regulated to
preserve the hexagonal phase propensity in
a manner entirely analogous to PE (Rilfors
et al, 1994). The regulation of the tendency
to form the hexagonal phase is observed in
response to membrane perturbing agents
other than temperature such as alcohols and
detergents, and by alterations in membrane
acyl chain composition that influence phospholipid shape (Lindblom et al, 1993; Osterberg et al, 1995). Thus the tendency of
membranes to form the hexagonal phase is
regulated by the modulation of the ratio of
hexagonal phase-forming to lamellar phaseforming lipids. For animals, this corresponds to the PE/PC ratio.
The precise regulation of the tendency of
membranes to form the hexagonal phase
during physiochemical challenge might be
a requirement for any number of physiological processes. Cellular activities involving
membrane fusion, and the regulation of certain enzymes are two such processes for
which some data have accumulated. Lipid
284
E. EUGENE WILLIAMS
and protein trafficking within the cell, as
well as processes involving membrane vesicles, are critically dependent on the appropriate ability of membranes to fuse to one
another. The tendency to form the hexagonal phase is an important determinant of
membrane fusibility (Chernomordik, 1996).
The membrane content of PE molecules
having ether-linked acyl groups (e.g., plasmalogens) may play a particularly important role in this regard as plasmalogens effectively promote membrane fusion (Lohner, 1996). The importance of modulating
the ability of membranes to fuse during
temperature adaptation has recently been
considered (Hazel, 1995).
Protein function is also regulated by the
tendency of the bilayer to form the reversed
hexagonal phase. The activity of protein kinase C is regulated by the differential binding of the enzyme to membranes with different hexagonal phase-forming lipid content. This enzyme is active over only a very
limited range of compositions (Senisterra
and Epand, 1993; Giorgione et al, 1995).
The probability of a transmembrane channel formed by the peptide alamethicin being
open is also strongly correlated with membrane content of hexagonal phase-forming
lipids (Keller et al, 1993). The peak of
phospholipase A2 activity occurs just before
the transition from lamellar to hexagonal
phase (Sen et al, 1991). Other proteins that
display a dependence on the tendency of
membranes to revert to the hexagonal phase
include rhodopsin (Brown, 1994), phospholipase C (Rao and Sundaram, 1993), prothrombin (Nelsestuen and Broderius, 1977),
serum amyloid P (Schwalbe et al, 1990),
the adenine nucleotide translocator (Streicher-Scott et al, 1994), CTP:phosphocholine cytidylyltransferase (Cornell, 1991),
Mg2+-ATPase, H+-ATPase, and ubiquininecytochrome c reductase (Yang and Hwang,
1996). Interestingly, the very enzymes that
are likely to be responsible for modulating
the hexagonal phase propensity also fall
into this category (Cornell and Arnold,
1996). Overall, a seemingly simple adjustment in membrane PE/PC ratio can have a
dramatic impact on cell function.
FIG. 3. Highly schematic representation of lipid-driven membrane domains. Each membrane domain comprises a unique set of lipids (and proteins) and can
exhibit unique properties including, among others, the
ability to regulate membrane-bound enzyme activities,
the tendency to form non-lamellar phases, and the capacity to fuse with the domains of other membranes.
LIPID-DRIVEN MEMBRANE DOMAINS
Despite the apparent freedom of lateral
movement furnished by the fluid mosaic
model of membrane structure (Singer and
Nicolson, 1972), the molecules of biological membranes are not randomly distributed
throughout the membrane. Instead, they are
found distributed non-randomly in a large
number of regions called domains. These
domains come in a variety of forms. Some
are large, relatively stable structures driven
and maintained by membrane-associated
proteins, such as, for example, the well
studied apical and basolateral regions of epithelial cells. Protein-driven membrane domains are relatively easy to study because
their stability allows them to be isolated and
analyzed. However, most of the membrane
is believed to consist of a large number of
less stable and rapidly changing associations of molecules that are driven mainly
by the non-ideal interactions of different
membrane lipids (Fig. 3). These lipid-driven domains are currently poorly understood, in large part because they have proven to be difficult to isolate. They probably
represent important functional units of biological membranes (Glaser, 1993), but
they have not yet been well characterized.
The non-ideal mixing of membrane lipids occurs at all levels of membrane complexity. Even a membrane composed of a
single phospholipid can display domain
structure. Single-component bilayers in the
liquid crystalline phase can exhibit regions
where so-called liquid ordered (condensed)
and liquid disordered (expanded) regions
LIPIDS AND MEMBRANE PHYSICAL PROPERTIES
separate from one another to form distinct
domains (Lee et al, 1974; Nag et al,
1991). When different lipid species are
mixed, molecules with fully saturated acyl
chains and the same head group tend to be
the most miscible but do not mix perfectly
(Lee, 1977). Differences in head group
composition and acyl chain unsaturation
add to the complexity of non-ideal interactions (Huang et al, 1993). The range of
possible mixing patterns can be quite elaborate. For example, 18:1/18:1-PC (a PC
molecule containing two oleoyl chains) is
fully miscible with 14:0/14:0-PC up to 25%
14:0/14:0-PC. Above 25% the lipids begin
to segregate into domains (Van Dijck et al.,
1977). Considering the structural diversity
of membrane lipids, it is easy to envision a
large population of lipid-driven domains in
the membranes of cells.
Cholesterol and docosahexaenoic acid
(DHA or 22:6), the longest and most unsaturated acyl chain that occurs commonly
in cell membranes (Salem et ah, 1986),
have considerable impact on the formation
of lipid domains in membranes. In model
membranes composed of a single phospholipid, cholesterol distributes differently between liquid ordered and liquid disordered
domains (Sankaram and Thompson, 1991).
Cholesterol is able to increase the molecular
order of membranes made up of phospholipids with saturated and monounsaturated
acyl chains (Demel et al., 1972). Mixtures
of cholesterol and these phospholipids are
fully miscible and interact freely (Pasenkiewicz-Gierula et al., 1991; Stillwell et al,
1996). In contrast, cholesterol is unable to
increase order in more unsaturated membranes and has no affect at all on highly
unsaturated lipids such as those containing
DHA (Stillwell et al., 1996). Mixtures of
cholesterol and polyunsaturated phospholipids tend to segregate away form one another and to form separate membrane domains (Demel et al., 1972; PasenkiewiczGierula et al., 1990; Stillwell et al, 1993;
Stillwell et al, 1996). This difference in behavior is thought to be due to geometric
constraints; cholesterol can only interact favorably with lipids containing a A-9 pocket,
i.e., lipids with one acyl chain having no
double bond between the glycerol backbone
285
and the ninth carbon down the chain. This
A-9 pocket allows cholesterol to align
closely with the phospholipid molecule (Pasenkiewicz-Gierula et al, 1990; Stillwell et
al, 1994).
In addition to the interactions with phospholipid acyl chains, cholesterol also interacts differently with different phospholipid
classes (i.e., different head groups) in the
order of preference sphingomyelin > phosphatidylserine = phosphatidylglycerol >
PC » PE (Van Dijck, 1979). Cholesterol
also preferentially segregates into PC domains over PE domains (Van Dijck et al,
1976; Demel et al, 1977; Van Dijck, 1979;
Yeagle and Young, 1986). The most unfavorable interaction is between cholesterol
and PE molecules containing DHA as an
acyl component. These differential interactions of phospholipids and cholesterol are
probably responsible for the observed differences in the cholesterol content of cellular organelles. The cholesterol content of
membranes from different cellular organelles can be reproduced almost exactly by
allowing cholesterol to partition passively
into vesicles made of the pure phospholipid
extracts of the membranes. Thus the "affinity" of a given membrane for cholesterol
may dictate its cholesterol content (Wattenberg and Silbert, 1983). The transbilayer
distribution of cholesterol is also dependent
on the polyunsaturate content of the membrane. Under normal culture conditions the
cell membranes of a particular fibroblast
cell line (LM fibroblasts) contain no polyunsaturated lipids, and 70% of the cholesterol located in the plasma membrane resides in the inner leaflet. When grown in
culture medium supplemented with polyunsaturates, the cells incorporate the polyunsaturates into their membrane lipids and the
transbilayer distribution of cholesterol becomes completely reversed; 70% of the
plasma membrane cholesterol is found in
the outer leaflet (Sweet and Schroeder,
1988). If the polyunsaturates are selectively
incorporated into the inner leaflet (Sweet
and Schroeder, 1988), the reversal of the
transbilayer distribution of cholesterol
might be due to unfavorable interactions
between cholesterol and the polyunsaturates.
286
E. EUGENE WILLIAMS
DHA is known to promote domain formation in both model membranes and cells
(Stillwell et al, 1993; Stillwell et al,
1996). In a variety of poikilotherms, membrane DHA levels are strongly negatively
correlated with acclimation temperature
(Williams and Hazel, 1993). In higher animals DHA is present in much smaller quantities, but represents a major component of
several specialized tissues including brain,
sperm, and the rod outer segment, where it
can contribute up to 50% of the total fatty
acid composition (Salem et al., 1986). Unlike other acyl groups, DHA is tenaciously
retained during periods of dietary co-3 deficiency and starvation (Wiegand et al.,
1991; Salem et al, 1986; Stinson et al,
1991). In humans, changes in membrane
DHA content are associated with the alleviation of a number of serious but apparently unrelated diseases including multiple
sclerosis (Bernsohn and Stephanides,
1967), malaria (Levander et al, 1989), diabetes (Waldhausl et al, 1989), autoimmune disease (Fernandes, 1989) and a variety of cancers (Pascale et al, 1993; Hendrickse et al, 1995). The basis of DHA's
diverse functions is unclear but there may
be an important link between DHA's ability
to induce the formation of lipid domains in
membranes and its biological activity. For
instance, the reported influence of DHA on
the activity of several enzymes may be due
to a direct effect of the fatty acid on the
membrane (Vaidyanathan et al, 1994) but
is more likely related to its ability to induce
lipid domains when present as an acyl component of phospholipids (Cornell, 1991;
Holian and Nelson, 1992; Hexeberg et al,
1994; Giorgione et al, 1995). Also, polyunsaturates other than DHA influence enzyme
activity by altering membrane domain
structure (Incerpi et al, 1992). Based on
these combined observations, the polyunsaturate content of a membrane must be
considered the primary determinant of the
membrane's domain structure.
In addition to the regulation of enzyme
activity, there are other important functional
consequences of alterations in lipid-driven
domains in cell membranes. Most of the
physiological functions attributable to the
tendency of a membrane to form the hex-
agonal phase described above can also be
attributed to individual membrane domains.
Different membrane domains can have different tendencies to form the reversed hexagonal phase. Thus membrane fusion and
lipid and protein sorting might also depend
critically on the domain structure of the
membranes involved. Also, a number of reports in the literature point to breaks in Arrhenius plots of membrane order or enzyme
activity that occur well away from the temperatures of the lamellar to gel phase or lamellar to hexagonal phase transitions.
These breaks may correspond to the temperature at which the structure of lipid-driven domains is altered (Lee et al, 1974).
Glycolipid domains are thought to form the
basis for vesicle formation in the Golgi network, and proteins destined for the apical
surface of epithelial cells are transported
along with these glycolipid domains (Dupree et al, 1993). Lipid-driven domains in
a membrane can create localized areas of
altered permeability and can exhibit modified rates of transbilayer diffusion of phospholipids (flip-flop) along their borders
(Shimshick and McConnell, 1973). Because
of the non-random lipid composition of
membrane domains, membrane proteins are
also likely to be segregated resulting in areas of localized receptor domains, enzyme
activity, product concentrations, and antigen expression (Stillwell et al, 1993). Thus
changes in the physiochemical environment
that are capable of altering the lipid-driven
domain structure of a membrane can have
profound effects on cell function, and the
maintenance of proper domain structure
may therefore be crucial for survival.
CONCLUSIONS
Faced with changes in their physiochemical environment, the cells of many organisms alter the lipid composition of their
membranes. This membrane restructuring
has been thought to arise from the necessity
of maintaining membrane order or fluidity.
However, the most consistently observed
changes in membrane lipid composition under these conditions, altered PE/PC and
polyunsaturate content, are not always as
effective as other means (for example, altered content of acyl chains containing a
LIPIDS AND MEMBRANE PHYSICAL PROPERTIES
single double bond) at maintaining membrane order. Thus membrane restructuring
may be responsible for the conservation of
some other, perhaps equally important,
membrane property. The hexagonal phaseforming propensity of a membrane is a
property that establishes the fusion potential
of the membrane and regulates the activity
of a variety of enzymes. The tendency of a
membrane to form the hexagonal phase is
a quality that is ardently defended under a
variety of environmental circumstances.
This defense is achieved through alterations
in the ratio of hexagonal phase-forming lipids to lamellar phase-forming lipids, which
for animals translates to alterations in
PE/PC.
Similarly, the precise structure of the lipid-driven domains existing in a given membrane is a key property that may be responsible for a variety of cell functions including vesicle formation and enzyme regulation. Because the idea of lipid-driven
domains is relatively new, the number of
physiological functions requiring their involvement has yet to be established. Also
unknown is how these structures are influenced by changes in the physiochemical environment. What is becoming clear is that
lipid-driven domains are profoundly influenced by the polyunsaturate and cholesterol
content of the membrane. A satisfying explanation for the accumulation of polyunsaturates in the membranes of cold-acclimated species has been elusive, and the role
of cholesterol in the process of thermal adaptation has been equally enigmatic (e.g.,
Crockett and Hazel, 1995). Both explanations may have their basis in the preservation of the structure of lipid-driven domains
in the membrane. The involvement of membrane domains in important cell functions
and the apparent complexity of membrane
domain structure implies that some sort of
adjustment in these structures will be inevitable when cells are faced with fluctuations in their physiochemical environment.
The nature of these adjustments await further study.
ACKNOWLEDGMENTS
It is my pleasure to thank William Stillwell and Laura J. Jenski for their support
287
and for lively discussions on membranes
and membrane physical properties. Thanks
also to the editor and two anonymous reviewers whose suggestions and useful comments improved this paper.
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Corresponding Editor: Gary C. Packard