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How do lipid-soluble substances diffuse through the cell membrane?

How do lipid-soluble substances diffuse through the cell membrane?



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It's said that water-soluble substances can diffuse through cell membrane with less ease than lipid-soluble substances because the former encounters impedance in the hydrophobic region of the phospholipid bilayer. However, does the same logic not apply for hydrophobic substances, in that they cannot traverse the hydrophilic outer/inner surfaces of the plasma membrane? How would they be able to enter or leave the cell with greater ease?


See this paragraph and image from The Cell: A Molecular Approach. 2nd edition.:

During passive diffusion, a molecule simply dissolves in the phospholipid bilayer, diffuses across it, and then dissolves in the aqueous solution at the other side of the membrane… Passive diffusion is thus a nonselective process by which any molecule able to dissolve in the phospholipid bilayer is able to cross the plasma membrane and equilibrate between the inside and outside of the cell. Importantly, only small, relatively hydrophobic molecules are able to diffuse across a phospholipid bilayer at significant rates (Figure 12.15). Thus, gases (such as O2 and CO2), hydrophobic molecules (such as benzene), and small polar but uncharged molecules (such as H2O and ethanol) are able to diffuse across the plasma membrane. Other biological molecules, however, are unable to dissolve in the hydrophobic interior of the phospholipid bilayer. Consequently, larger uncharged polar molecules such as glucose are unable to cross the plasma membrane by passive diffusion, as are charged molecules of any size (including small ions such as H+, Na+, K+, and Cl-). The passage of these molecules across the membrane instead requires the activity of specific transport and channel proteins, which therefore control the traffic of most biological molecules into and out of the cell.

As shown in above paragraph, molecules have to dissolve in phospholipid bilayer to diffuse through it. But since the hydrophilic part is already interacting with water, so dissolving is mainly for the hydrophobic part. Now, since hydrophobic part is non-polar, so it can dissolve only non-polar substances (like dissolves like). Thus, small gases like O2, CO2 and non-polar molecules like benzene easily dissolve in hydrophobic part and diffuse through it. Also, molecules like water and ethanol can also dissolve in it in small amounts due to their small size and very less polarity. That's why only some molecules of water can diffuse passively, large amount of water would require aquaporins. Now, since bigger molecules like glucose have large size and high polarity, they cannot dissolve in the membrane and thus require transmembrane channels even for diffusion. Similar case is with ionic substances too: they require ion channels for their diffusion.

Hope this helps. Comment below if you have any further doubts.


Cell Diffusion: How Do Substances Diffuse Through Cells

Diffusion is a process that occurs when a substance such as water, molecules, and ions, which are usually needed for various cellular processes, enter and leave cells. The way that cell diffusion happens is by molecules moving from an area of high concentration to an area of low concentration. This usually occurs until both molecules have the same amount of the substance and it is distributed evenly.

Cell diffusion can have different rates, and it is a process that is studied heavily in biology. If you want to learn more about cell diffusion and how it works, then you should check out the Udemy course, An Introduction to Basic Biology.


How are free fatty acids transported in membranes? Is it by proteins or by free diffusion through the lipids?

Although transport of long-chain free fatty acids (FFAs) into cells is often analyzed in the same way as glucose transport, we argue that the transport of the lipid-soluble amphipathic FFA molecule must be viewed differently. The partitioning of FFAs into phospholipid bilayers and their interfacial ionization are particularly relevant to transport. We summarize new data supporting the diffusion hypothesis in simple lipid bilayers and in plasma membranes of cells. Along with previous supporting data, the new data indicate that transport of FFAs through membranes could occur rapidly by flip-flop of the un-ionized form of the FFA. It appears that, at least for the adipocyte, passive diffusion guarantees fast entry and exit of FFAs at both low and high concentrations. Although there are several candidate proteins for the membrane transport of FFAs, most of these proteins have other established functions. Thus, unlike the glucose transporters, these proteins would not be single-function proteins. Definitive proof of their function as FFA transporters awaits their reconstitution into simple model systems.


Plasma Membrane Hormone Receptors

Amino acid derived hormones and polypeptide hormones are not lipid-derived (lipid-soluble) and therefore cannot diffuse through the plasma membrane of cells. Lipid insoluble hormones bind to receptors on the outer surface of the plasma membrane, via plasma membrane hormone receptors. Unlike steroid hormones, lipid insoluble hormones do not directly affect the target cell because they cannot enter the cell and act directly on DNA. Binding of these hormones to a cell surface receptor results in activation of a signaling pathway this triggers intracellular activity and carries out the specific effects associated with the hormone. In this way, nothing passes through the cell membrane the hormone that binds at the surface remains at the surface of the cell while the intracellular product remains inside the cell. The hormone that initiates the signaling pathway is called a first messenger, which activates a second messenger in the cytoplasm, as illustrated in Figure 2.

Figure 2. The amino acid-derived hormones epinephrine and norepinephrine bind to beta-adrenergic receptors on the plasma membrane of cells. Hormone binding to receptor activates a G-protein, which in turn activates adenylyl cyclase, converting ATP to cAMP. cAMP is a second messenger that mediates a cell-specific response. An enzyme called phosphodiesterase breaks down cAMP, terminating the signal.

One very important second messenger is cyclic AMP (cAMP). When a hormone binds to its membrane receptor, a G-protein that is associated with the receptor is activated G-proteins are proteins separate from receptors that are found in the cell membrane. When a hormone is not bound to the receptor, the G-protein is inactive and is bound to guanosine diphosphate, or GDP. When a hormone binds to the receptor, the G-protein is activated by binding guanosine triphosphate, or GTP, in place of GDP. After binding, GTP is hydrolysed by the G-protein into GDP and becomes inactive.

The activated G-protein in turn activates a membrane-bound enzyme called adenylyl cyclase. Adenylyl cyclase catalyzes the conversion of ATP to cAMP. cAMP, in turn, activates a group of proteins called protein kinases, which transfer a phosphate group from ATP to a substrate molecule in a process called phosphorylation. The phosphorylation of a substrate molecule changes its structural orientation, thereby activating it. These activated molecules can then mediate changes in cellular processes.

The effect of a hormone is amplified as the signaling pathway progresses. The binding of a hormone at a single receptor causes the activation of many G-proteins, which activates adenylyl cyclase. Each molecule of adenylyl cyclase then triggers the formation of many molecules of cAMP. Further amplification occurs as protein kinases, once activated by cAMP, can catalyze many reactions. In this way, a small amount of hormone can trigger the formation of a large amount of cellular product. To stop hormone activity, cAMP is deactivated by the cytoplasmic enzyme phosphodiesterase, or PDE. PDE is always present in the cell and breaks down cAMP to control hormone activity, preventing overproduction of cellular products.

The specific response of a cell to a lipid insoluble hormone depends on the type of receptors that are present on the cell membrane and the substrate molecules present in the cell cytoplasm. Cellular responses to hormone binding of a receptor include altering membrane permeability and metabolic pathways, stimulating synthesis of proteins and enzymes, and activating hormone release.


The Cell Membrane

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The Cell membrane surrounds all living cells and is the most important organelle, there is also a similar plasma membrane that surrounds all the organelles except for the ribosome.

The membrane controls how and what substances can move in and out of the cell/organelle The structure of the membrane is often referred to as the “Fluid Mosaic Model” this is because of the way it is structured It is composed of phospholipids, proteins, and carbohydrates, which are arranged in a fluid mosaic structure. The phospholipids are arranged in a “bilayer”.With their hydrophilic (water attracting) phosphate heads facing outwards and their hydrophobic (water fearing) tails facing in towards the middle of the bilayer. The hydrophobic layer acts as a barrier to all but the smallest molecules and effectively isolating the two sides of the membranes.

Some membranes contain phospholipids with different fatty acids, which affect the strength and flexibility. Animal cells also have cholesterol linking the fatty acids together and so stabilising and strengthening then membrane The proteins usually span from one side of the bilayer to the other. These are called integral proteins.But some sit on one side of the bilayer, these are called peripheral proteins.

Proteins comprise approximately 50% of the mass of the membrane. The integral proteins (ones which span across the whole bilayer) are usually involved in the transporting of substances across the membrane. The proteins that are on the inside of the bilayer are often attached to the cytoskeleton and are involved in maintaining the cell’s shape. They may also be enzymes for catalysing reactions. The proteins on the outside act as receptors, with a specific binding site, where hormones or other chemicals can bind.The Carbohydrates are found on the outer surface and are attached to the proteins or sometimes the phospholipids.

Proteins with a carbohydrate attaches are known as glycoproteins and phospholipids with a carbohydrate attached are called glycolipids. REMEMBER THAT A MEMBRANE IS NOT JUST A LIPID BILAYER, BUT COMPRISES THE LIPID, PROTEIN AND CARBOHYDRATE PARTS! There are 5 main methods by which substances can move across the membrane LIPID DIFFUSION- this method works for substances, which can diffuse directly through lipid bilayer.The only substances that are able to do this are lipid-soluble such as steroids or very small molecules such as H2O, O2, and CO2. This is a type of passive transport (passive diffusion process) and therefore no energy is required. This also means that the cell cannot control lipid diffusion.

OSMOSIS- this is the diffusion of water across a membrane. It is just the same as Lipid Diffusion but because water so important and abundant in cells it has its own name. PASSIVE TRANSPORT (FACILITATED DIFFUSION)-passive transport is the transport of substances across a membrane by a trans-membrane protein.This is a specific type of diffusion so the substance must contain the right protein. This also requires no energy.

Passive transport requires two types of protein. Channel proteins- these form a water-filled pore or channel in the membrane. This allows charged substances (eg ions) to diffuse across the membrane. Carrier Proteins- these have a binding site for a specific solute. Once it has bound the protein “flips” to allow the solute to enter/exit the membrane.

This means that the site is always open to one side of the membrane.The substance will only bind where there is a high concentration and be released where there is a low concentration. ACTIVE TRANSPORT (or PUMPING)- This where the protein binds to the molecule on one side of the membrane, and then changes shape to deliver it to the other side. Because they are specific there is a different protein pump for every molecule to be transported.

Because the proteins are ATPase and catalyse the splitting of ATP they release energy, therefore making it an active process (requires energy). It also the ONLY method where a substance can be moved UP its concentration gradient.VESICLES- all the previous processes apply to only small molecules. This is the process used for larger molecules such as proteins, polysaccharides, and nucleotides and sometimes even whole cells. There are two types of way a vesicle can work.

Endocytosis- this is the transport of materials into cells. The membrane folds itself around the substance then pinches off to trap the substance inside it. Exocytosis- this is the reverse of endocytosis. The materials are transported out of the cell and are usually enclosed in a vesicle from the RER or the Golgi Body.


How do lipid-soluble substances diffuse through the cell membrane? - Biology

8 The Lipid Solubility, Diffusion Through Membranes and Drug Distribution Page!

Biological membranes exhibit semipermeability (selective permeability). Membranes tend to exclude certain substances from entering or leaving a cell. As the majority of the surface area of a membrane is composed of phospholipids, substances diffusing through membranes must have some degree of lipid solubility. Thus, the factors that determine the ability of a substance to diffuse through membranes are the factors which determine the lipid solubility of the diffusing substance. Ultimately, these factors determine the rate of absorption and extent of distribution of drug molecules in the body.

8 Some factors determining lipid solubility and extent of drug distribution throughout the body are:

i) chemical nature of the molecule (brief explanation)
ii) atomic or molecular formula weight (directly proportional to size) (brief explanation)
iii) valence or charge (polar versus nonpolar) (brief explanation)
iv) sphere of hydration (charge density and effective diameter) (brief explanation)
v) prevailing concentration gradient (slope or steepness of the gradient) (brief explanation)
vi) pKa of the diffusing substance and the pH of the environment (brief explanation)
vii) route of administration (brief explanation)

8 Diffusion Coefficient and Apparent Volume of Distribution: Lipids (fats), including steroid hormones and lipid soluble vitamins are described as "fat soluble." The steroid hormones are small, uncharged, cholesterol-based molecules which diffuse easily through membranes. The lipid solubility of drugs, toxins, nutrients and vitamins are often expressed as "diffusion coefficient" or "apparent volume of distribution" (Vd). The diffusion coefficient refers to the rate of diffusion of a given molecule through vegetable oil, usually corn or peanut oil (as lipid solubility increases, the diffusion coefficient increases from 0 to 1 substances with diffusion coefficients approaching 1.0 are highly lipid soluble and easily diffuse across membranes).

8 Remember that a drug is not said to have entered the body until it enters the bloodstream. That means that drugs appear first in the plasma, next in the ISF and finally in the ICF.

The apparent volume of distribution (Vd) is a bit more complex. Vd indicates the theoretical volume of water in which a drug would have to be distributed if the drug was distributed evenly and at the same concentration found in the bloodstream (plasma). That sounds complicated. and it can be. and here is why. Some drugs are so highly lipid soluble that they quickly leave the bloodstream and enter adipose cells. Drugs with very high lipid solubility, then, may quickly and nearly completely evacuate the bloodstream. The result is that the concentration of the drug is so low in the bloodstream, that if the drug were "really" to be evenly distributed in solution at the same concentration as found in the bloodstream, the drug would have to be distributed in a theoretical volume of water many times greater than the actual volume of fluid in the body. and this is where the term "apparent" volume of distribution comes from. because sometimes, the "apparent" volume of water required would be greater than the amount of water present in the body.

We can determine apparent volume of distribution (Vd) by dividing the dose of drug administered by the amount of the drug in the bloodstream following distribution of the drug.

Suppose that we injected someone with a total "dose" (i.v. bolus) of 10 grams of aspirin. Following distribution, we found a plasma concentration of 0.5 mg/ml in plasma. If we divide 10 g (10,000 mg) by 0.55 mg. that is a dilution factor of . .. 10,000 divided by 0.5 = 20,000 . But we know that a mg of water has a volume of 1 ml. That means. our drug must have been distributed to a theoretical volume of of 20,000 ml's or 20 liters of water . Our patient had a body mass of 50 kg. When we divide the theoretical volume of water in which the aspirin was distributed (20 L) by the mass of the patient (50 kg), we get a theoretical volume of distribution of 0.4 L/kg of body mass .

Think about the value of 0.4 L/kg of body weight. we know that the average human is about 55% water. which would represent 0.55 L of water per kg of body weight. if we divide 0.4 L by 0.55 L. that gives us a value of 0.73. or 73%. telling us that aspirin is distributed to about 73% of the water in the body. that is a fairly well distributed drug, but certainly not a highly lipid soluble drug. Now. if we determined a volume of distribution in excess of 0.55 L per kg, that is a very well distributed drug. If apparent volume of distribution increased beyond this level. to 1.0 L per kg of body weight or more, we could assume that the drug in question is a very highly lipid soluble drug, and is accumulating in fat tissues.

But determining a specific moment at which to take a measure of concentration of the drug in the blood is impossible. So, to get around this problem, we take multiple measures of the drug concentration in the blood, and then multiply the area under the concentration versus time curve by the linear portion of the curve showing elimination rate of the drug from circulation. Alternately, we can use the flat, terminal portion of the plasma drug concentration line to extrapolate back to a hypothetical blood concentration at time zero (the moment of administration), and simply divide the dose of drug administered by this extrapolated zero time value.

8 Note about gases: Most gases diffuse easily through aqueous solutions and membranes, although some diffuse more easily (eg. CO2 is about 20 times more diffusible in water than is O2). This is great in terms of delivery of O2 and removal of CO2 but causes problems when people are exposed to toxic gases, which also diffuse easily into the tissues.


Selective Permeability

Plasma membranes are asymmetric, meaning that despite the mirror image formed by the phospholipids, the interior of the membrane is not identical to the exterior of the membrane. Integral proteins that act as channels or pumps work in one direction. Carbohydrates, attached to lipids or proteins, are also found on the exterior surface of the plasma membrane.

These carbohydrate complexes help the cell bind substances in the extracellular fluid that the cell needs. This adds considerably to the selective nature of plasma membranes.

Recall that plasma membranes have hydrophilic and hydrophobic regions. This characteristic helps the movement of certain materials through the membrane and hinders the movement of others. Lipid-soluble material can easily slip through the hydrophobic lipid core of the membrane. Substances such as the fat-soluble vitamins A, D, E, and K readily pass through the plasma membranes in the digestive tract and other tissues. Fat-soluble drugs also gain easy entry into cells and are readily transported into the body’s tissues and organs. Molecules of oxygen and carbon dioxide have no charge and pass through by simple diffusion.

Polar substances, with the exception of water, present problems for the membrane. While some polar molecules connect easily with the outside of a cell, they cannot readily pass through the lipid core of the plasma membrane. Additionally, whereas small ions could easily slip through the spaces in the mosaic of the membrane, their charge prevents them from doing so. Ions such as sodium, potassium, calcium, and chloride must have a special means of penetrating plasma membranes. Simple sugars and amino acids also need help with transport across plasma membranes.


Endocytosis and exocytosis

Wherever molecules are of a substantial size, the use of an exchange protein or ATP-powered pump to move them becomes impractical. Consider, that the typical ATP-powered pump is a 100 kDa protein. If what you are trying to move is also a 100 kDA protein, obviously another method is required. That method is endocytosis. On some fundamental level one might classify endocytosis as a type of primary active transport. However, instead of an ATP-cracking protein undergoing a conformal change and pushing a molecule through the membrane, the entire membrane undergoes a conformal change in order to envelop and consume the molecule, bringing it into the cell in the form of an endosome.

This is not a peculiarity of transporting molecules from outside of the cell into the inside. Vesicular transport is the main method of getting a large molecule from A to B within the cell, and most organelles exchange their substrates in this fashion. The process of internalising molecules in this fashion is complex, requiring many steps. It is well described in such freely available online resources as this chapter of The Cell. In summary, a whole array of molecular machinery is deployed to manipulate these vesicles, and the process is relatively energy-expensive.


Year 11 Misadventures

1. Understand the random movement of molecules down a concentration gradient.

As you should know by now, molecules diffuse from an area of high concentration to an area of low concentration. (To find out more, review my earlier post on diffusion and osmosis.)

One common misconception with diffusion is that particles move to an area of low concentration. This isn't strictly true. Molecules don't wake up in the morning and think "hmm, looks like there's less of us over there, better get moving then." They move around randomly, dispersing themselves over the available area. Throughout this process of dispersion, you get roughly even amounts of the molecule throughout the area. Hence the net movement of molecules is from a high concentration to a low concentration, but the motions of individual molecules is still random.

2. Understand the importance of molecular weight, lipid solubility and charge on membrane permeability.

Molecules with a lower molecular weight tend to diffuse more rapidly, probably because they don't have to "push aside" other molecules as much.

Lipid solubility is another important factor influencing membrane permeability. Molecules that are more lipid soluble are more permeable as they are soluble in the cell membrane (which is a lipid bilayer).

Charged particles, as they tend to be hydrophilic and lipid insoluble, have a very low permeability. They can exert their effects by binding to receptors on the cell surface (see my post on biochemical messengers) or by diffusing through ion channels (I'll talk about these later).

3. Define the concept of flux and its relationship to membrane permeability.

Flux is the movement of molecules across a given area. If you are looking at the flux across the membrane, you are essentially also looking at the membrane permeability (i.e. the ability of molecules to move across the membrane). Hence flux is directly proportional to membrane permeability.

4. Contrast the diffusion of solutes through a membrane and through a pore/channel.

I'm not really sure what there is to contrast here. While lipid-soluble substances diffuse through the membrane, ions and other charged substances often have to travel through channels. The general principles still apply, but sometimes the channels can open and close.

5. Understand the concepts of osmolarity/osmolality and tonicity.

Osmolarity is the number of particles dissolved in a litre of solution, while osmolality is the number of particles dissolved in a kilogram of solution. These terms are pretty much interchangeable on Earth.

Tonicity, on the other hand, is the ability of a solution to affect a cell. A hypotonic solution will cause a cell to burst while a hypertonic solution will cause a cell to lyse. Sometimes a hypotonic solution will also be hypoosmotic, but not always. Sometimes a solution might start out with the same osmolarity as the cell, but it contains certain particles that can diffuse into the cell, thus changing the osmolarities of the cell and the solution.

6. Describe the distribution of water and solute concentrations in the body compartments.

I'm not really sure what is required here. There's a diagram in the slides that shows that most water (roughly 25L) is in the cells, followed by extracellular fluid (roughly 13L), followed by blood plasma (roughly 3L). There's also another 1L marked "transcellular fluid," which, according to Google, is basically fluid that is between cells but separated off from the main interstitial fluid. All but the transcellular fluid has an osmolarity of around 290 mOsm (i.e. roughly the same amount of particles dissolved in all of the fluids in the body).

7. Understand the importance of osmolality and hydrostatic pressure in the regulation of fluid balance.

As blood travels to the tissues, water diffuses into the interstitial fluid via osmosis (a process that is partially counteracted by hydrostatic forces). In the capillaries in the arterial side, the blood pressure is much greater, causing more water to diffuse into the interstitial fluid than out of it (or at least that's my understanding). The opposite occurs in the venous capillaries. This process mostly "balances out" the movement of fluid into and out of the interstitial space, with any extra fluid picked up by the lymph system. If not enough water diffuses back into the blood on the venous side, however, water can build up in the interstitial space, resulting in swelling, or oedema.


Some very small, non-polar molecules, including oxygen and carbon dioxide, can pass directly through the cell membrane in a process called simple diffusion. In the cafeteria example, it would be as if there were only a line painted on the floor to separate one lunch line from the other. Students would simply step across the line to get from the crowded area to the open space. Water molecules, although polar, are small enough to pass through the cell membrane passively. The diffusion of water down the concentration gradient is called osmosis.

Because of their size and polarity, many molecules need help moving across the cell membrane. Proteins embedded in the membrane provide a gateway for diffusion. When molecules move down a concentration gradient through an open protein pore, the process is called channel diffusion. In the cafeteria example, the channel protein would be an open door between rooms.


Some substances can cross the cell-surface membrane of a cell by simple diffusion through the phospholipid bilayer. Describe other ways by which substances cross this membrane.

Other ways that substances can cross the plasma membrane include facilitated transport, where molecules or ions must interact with a channel/carrier protein to be transported across the membrane, down a concentration gradient, which doesn't require energy. Another method is active transport, where molecules are moved via protein pumps, which requires energy in the form of ATP, and which may move up a concentration gradient. In addition, water may move across membranes via osmosis, from high to low water potential, via aquaporins or water channels. Alternatively, substances contained within vesicles may exit the cell via fusion of the vesicular membrane with the plasma membrane, leading to the release of its contents to the extracellular space. Extracellular material may also enter the cell via phagocytosis, which involves the cell membrane surrounding and engulfing the substance, to form an intracellular vesicle or vacuole.