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Transport mechanisms: Active and passive


An important function of the membrane is to withhold unwanted molecules, while permitting entry of molecules necessary for cellular metabolism

The permeability of substances across cell membrane is dependent on their solubility in lipids and not on their molecular size. Water soluble compounds are generally impermeable and require carrier mediated transport. An important function of the membrane is to withhold unwanted molecules, while permitting entry of molecules necessary for cellular metabolism








Transport mechanisms are classified into

1. Passive transport

1-A. Simple diffusion 1-B. Facilitated diffusion. 1-C. Ion channels are specialized carrier systems. They allow passage of molecules in accordance with the concentration gradient.

2. Active transport

3. Pumps can drive molecules against the gradient using energy.


Simple Diffusion Solutes and gases enter into the cells passively. 

They are driven by the concentration gradient. The rate of entry is proportional to the solubility of thatsolute in the hydrophobic core of the membrane. Simple diffusion occurs from higher to lower concentration. This does not require any energy. However, it is a very slow process.


Facilitated Diffusion. 

This is a carrier mediated process. Important features of facilitated diffusion are: a. The carrier mechanism could be saturated which is similar to the Vmax of enzymes. b. Structurally similar solutes can competitively inhibit the entry of the solutes. c. Facilitated diffusion can operate bidirectional. d. This mechanism does not require energy but the rate of transport is more rapid than simple diffusion process. e. The carrier molecules can exist in two conformations, Ping and Pong states.

In the pong-state, the active sites are exposed to the exterior, when the solutes bind to the specific sites. Then there is a conformational change. In the ping state, the active sites are facing the interior of the cell, where the concentration of the solute is minimal. This will cause the release of the solute molecules and the protein molecule reverts to the pong state. By this mechanism the inward flow is facilitated, but the outward flow is inhibited. Hormones regulate the number of carrier molecules. For example, glucose transport across membrane is by facilitated diffusion involving a family of glucose transporters


Aquaporins
 
They are water channels. They are a family of membrane channel proteins that serve as selective pores through which water crosses the plasma membranes of cells. They form tetramers in the cell membrane, and facilitate the transport of water They control the water content of cells. Agre and MacKinnon were awarded Nobel prize for chemistry in 2003 for their contributions on aquaporins and water channels. Diseases such as nephrogenic diabetes insipidus is due to impaired function of these channels

Channelopathies are a group of disorders that result from abnormalities in the proteins forming the ion pores or channels. A few examples are cystic fibrosis (chloride channel), Liddle's syndrome (sodium channel) and periodic paralysis (potassium channel)
 
Ion Channels Membranes have special devices called ion channels.
 
Ion channels are trans membrane proteins that allow the selective entry ofvarious ions.  These channels are for quick transport of electrolytes such as Ca++, K+, Na+ and Cl--. These are selective ion conductive pores. Ion channels are specialized protein molecules that span the membranes.


The channels generally remain closed, but in response to stimulus, they open allowing rapid flux of ions down the gradient. This may be compared to opening of the gate of a cinema house, when people rush to enter in. Hence this regulation is named as "gated". Such ion channels are important for nerve impulse propagation, synaptic transmission and secretion of biologically active substances from the cells. Ion channels are different from ion transport pumps described below.






Ligand Gated Channels
 
Ligand gated channels are opened by binding of effectors. The binding of a ligand to a receptor siteon the channel results in the opening (or closing) of the channel. The ligand may be an extracellular signalling molecule or an intracellular messenger.

Acetyl choline receptor is the best example for ligand gated ion channel. It is present in postsynaptic membrane. It is a complex of 5 subunits, consisting of acetyl choline binding site and the ion channel. Acetyl choline released from the presynaptic region binds with the receptors on the postsynaptic region, which triggers opening of the channel and influx of Na+. This generates an action potential in the postsynaptic nerve. The channel opens only for a millisecond, because the acetyl choline is rapidly degraded by acetyl cholinesterase.


Calcium channels
 
Under appropriate stimuli calcium channels are opened in the sarcoplasmic reticulum membrane, leading to an elevated calcium level in the cytosol of muscle cells. Calcium channel blockers are therefore widely used in the management of hypertension.

Amelogenin, a protein present in enamel of teeth has hydrophobic residues on the outside.
 
A 27 amino acid portion of amelogenin functions as a calcium channel.Phosphorylation of a serine residue of the protein opens the calcium channel, through which calcium ions zoom through and are funnelled to the mineralization front. The amelogenin is used for the formation of calcium hydroxy apatite crystals.


Voltage Gated Channels
 
Voltage gated channels are opened by membrane depolarization. The channel is usually closed in the ground state. The membrane potential change (voltage difference) switches the ion channel to open, lasting less than 25 milliseconds. In voltage gated channels, the channels open or close in response to changes in membrane potential. They pass from closed through open to inactivated state on depolarization. Once in the inactivated state, a channel cannot re-open until it has been reprimed by repolarization of the membrane.

Voltage gated sodium channels and voltage gated potassium channels are the common examples. These are seen in nerve cells and are involved in the conduction of nerve impulses. Ion channels allow passage of molecules in accordance with the concentration gradient. Ion pumps can transport molecules against the gradient.


Ionophores
 
They are membrane shuttles for specific ions. They transport antibiotics. Ionophores increase the permeability of membrane to ions by acting as channel formers. The two types of ionophores are; mobile ion carriers (e.g. Valinomycin) and channel formers (e.g. Gramicidin). They are produced by certain microorganisms and are used as antibiotics. When cells of higher organisms are exposed to ionophores, the ion gradient is dissipated. Valinomycin allows potassium to permeate mitochondria and so it dissipates the proton gradient; hence it acts as an uncoupler of electron transport chain
 

Sodium | Calcium pump| Uniport | symport | antiport


For instance, suppose the sugar glucose is more concentrated inside of a cell than outside. If the cell needs more sugar in to meet its metabolic needs, how can it get that sugar in?
Here, the cell can't import glucose for free using diffusion, because the natural tendency of the glucose will be to diffuse out rather than flowing in. Instead, the cell must bring in more glucose molecules via active transport. In active transport, unlike passive transport, the cell expends energy (for example, in the form of ATP) to move a substance against its concentration gradient.



The salient features of active transport are: 

  • This form of transport requires energy. About 40% of the total energy expenditure in a cell is used for the active transport system.
  • The active transport is unidirectional. 
  • It requires specialized integral proteins called transporters. 
  • The transport system is saturated at higher concentrations of solutes. e. The transporters are susceptible to inhibition by specific organic or inorganic compounds
Sodium Pump 
 
It is the best example for active transport. Cell has low intracellular sodium; but concentration of potassium inside the cell is very high. This is maintained by the sodium–potassium activated ATPase, generally called as sodium pump. The ATPase is an integral protein of the membrane. It has binding sites for ATP and sodium on the inner side and the potassium binding site is located outside the membrane. It is made up of two pairs of unequal subunits α2 β2. Both subunits of the pump (alpha and beta) span the whole thickness of membrane.

Calcium Pump

An ATP dependent calcium pump also functions to regulate muscle contraction. A specialized membrane system called sarcoplasmic reticulum is found in skeletal muscles which regulates the Ca++ concentration around muscle fibers. In resting muscle the concentration of Ca++ around muscle fibers is low. But stimulation by a nerve impulse results in a sudden release of large amounts of Ca++. This would trigger muscle contraction. The function of calcium pump is to remove cytosolic calcium and maintain lowcytosolic concentration, so that muscle can receive the next signal. For each ATP hydrolysed, 2Ca++ ions are transported.

Uniport, Symport and Antiport

Transport systems are classified as uniport, symport and antiport systems.
Uniport system carries single solute across the membrane, e.g. glucose transporter in most of the cells. Calcium pump is another example.

If the transfer of one molecule depends on simultaneous or sequential transfer of another molecule, it is called co-transport system. The active transport may be coupled with energy indirectly. Here, movement of the substance against a concentration gradient is coupled with movement of a second substance down the concentration gradient; the second molecule being already concentrated within the cell by an energy requiring process.

The co-transport system may either be a symport or an antiport. In symport, the transporter carries two solutes in the same direction across the membrane, e.g. sodium dependent glucose transporter. Phlorhizin, an inhibitor of sodium-dependent co-transport of glucose, especially in the proximal convoluted tubules of kidney, produces renal damage and results in renal glycosuria. Amino acid transport is another example for symport.

The antiport system carries two solutes or ions in opposite direction, e.g. sodium pump or chloride-bicarbonate exchange in RBC.

Secretory Vesicles and Exocytosis




Under appropriate stimuli, the secretory vesicles or vacuoles move towards and fuse with the plasma membrane. This movement is created by cytoplasmic contractile elements; the microtubule system. The inner membrane of the vesicle fuses with outer plasma membrane, while cytoplasmic side of vesicle fuses with cytoplasmic side of plasma membrane. Thus the contents of vesicles are externalized.

This process is called exocytosis or reverse pinocytosis. Release of trypsinogen by pancreatic acinar cells; release of insulin by beta cells of Langerhans and release of acetyl choline by presynaptic cholinergic nerves are examples of exocytosis. Often, hormones are the signal for exocytosis, which leads to calcium ion changes, triggerring the exocytosis.

Endocytosis

Endocytosis is the mechanism by which cells internalize extracellular macromolecules, to form an endocytic vesicle. This requires energy in the form of ATP as well as calcium ions in the extracellular fluid. Cytoplasmic contractile elements take part in this movement. In general, plasma membrane is invaginated, enclosing the matter. This forms the endocytic vesicle. The endocytosis may be pinocytosis or phagocytosis or receptor mediated endocytosis

Pinocytosis

Pinocytosis literally means ‘drinking by the cell'. Cells take up fluid by this method. The fluid phase pinocytosis is a nonselective process.

Receptor Mediated Endocytosis



The selective or adsorptive pinocytosis is receptor mediated; also called as absorptive pinocytosis. Low Density Lipoprotein (LDL) is a good example. LDL binds to the LDL receptor and the complex is later internalized. The cytoplasmic side of these vesicles are coated with filaments; mainly composed of Clathrin. These are called Clathrin coated pits. After the LDL-receptor complex is internalized, the receptor molecules are released back to cell surface; but the LDL is degraded by lysosomal enzymes. 

Several hormones are also taken up by the cells by receptor-mediated mechanism. The protein, Dynamin which has GTPase activity, is necessary for the internalisation of clathrin coated pits. Many viruses get attached to their specific receptors on the cell membranes. Examples are Influenza virus, Hepatitis B virus, polio virus and HIV. They are taken up by caveolae mediated processes. Caveolae mediated endocytosis is also known as potocytosis.

Phagocytosis

The term is derived from the Greek word "phagein" which means to eat. It is the engulfment of large particles such as bacteria by macrophages and granulocytes. They extend pseudopodia and surround the particles to form phagosomes. Phagosomes later fuse with lysosomes to form phagolysosomes, inside which the particles are digested. An active macrophage can ingest 25% of their volume per hour. In this process, 3% of plasma membrane is internalized per minute. The biochemical events accompanying phagocytosis is described as respiratory burst
 

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