Endoplasmic Reticulum
The cytoplasmic matrix is traversed by a complex network of inter-connecting membrane-bound vacuoles or cavities. often remain concentrated in the endoplasmic portion of the cytoplasm; therefore, known as endoplasmic reticulum, a name derived from the fact that in the light microscope it looks like a "net in the cytoplasm." (Eighteenth-century European ladies carried purses of netting called reticules).
The name "endoplasmic reticulum" was coined in 1953 by Porter, who in 1945 had observed it in electron micrographs of liver cells. Fawcet and Ito (1958), Thiery (1958) and Rose and Pomerat (1960) have made various important contributions to the endoplasmic reticulum.
The occurrence of the endoplasmic reticulum varies from cell to cell. The erythrocytes (RBC), egg and embryonic cells lack in the endoplasmic reticulum.
The spermatocytes have poorly developed endoplasmic reticulum. The adipose tissues, brown fat cells, and adrenocortical cells, interstitial cells of testes and cells of corpus luteum of ovaries, sebaceous cells and retinal pigment cells contain only smooth endoplasmic reticulum (SER). The cells of those organs which are actively engaged in the synthesis of proteins such as chinar cells of the pancreas, plasma cells, goblet cells and cells of some endocrine glands are found to contain rough endoplasmic reticulum (RER) which is highly developed. The presence of both SER and RER in the hepatocytes (liver cells) is reflective of the variety of the roles played by the liver in metabolism.
Morphology
Morphologically, the endoplasmic reticulum may occur in the following three forms : 1. Lamellar form or cisternae (A closed, fluid-filled sac, vesicle or cavity is called cisternae) 2. vesicular form or vesicle and 3. tubular form or tubules.
- Cisternae. The cisternae are long, flattened, sac-like, unbranched tubules having the diameter of 40 to 50 mm. They remain arranged parallely in bundles or stakes. PER usually exists as cisternae which occur in those cells of pancreas, notochord and brain.
- Vesicles. The vesicles are oval, membrane bound vacuolar structures having the diameter of 25 to 500mm. They often remain isolated in the cytoplasm and occur in most cells but especially abundant in the SER.
- Tubules. The tubules are branched structures forming the reticular system along with the cisternae and vesicles. They usually have the diameter from 50 to 190mm and occur almost in all the cells. Tubular form of ER is often found in SER and is dynamic in nature, i.e., it is associated with membrane movements, fission and fusion between membranes of cytocavity network (see Thorpe, 1984).
Ultra structure
The cavities of cisternae, vesicles and tubules of the endoplasmic reticulum are bounded by a thin membrane of 50 to 60 A0 thickness. The membrane of endoplasmic reticulum is fluid-mosaic like the unit membrane of the plasma membrane, nucleus, Golgi apparatus, etc. The membrane, thus, is composed of a bimolecular layer of phospholipids in which 'float' proteins of various sorts. The membrane of endoplasmic reticulum remains continuous with the membranes of plasma membrane, nuclear membrane and Golgi apparatus. The cavity of the endoplasmic reticulum is well developed and acts as a passage for the secretory products. Palade (1956) has observed secretory granules in the cavity of endoplasmic reticulum.
Sometimes, the cavity of RER is very narrow with two membranes closely apposed and is much distended in certain cells which are actively engaged in protein sysnthesis (e.g., acinar cells, plasma cells and goblet cells). Weibel et al. , 1969, have calculated that the total surface of ER contained in 1ml of liver tissue is about 11 square metres, two-third of which is or rough types (i.e., RER).
Types of Endoplasmic reticulum
Two types of endoplasmic reticulum have been observed in same or different types of cells which are as follows :
1. Agranular or Smooth Endoplasmic Reticulum
This type of endoplasmic reticulum possesses smooth walls because the ribosomes are not attached with its membranes. The smooth type of endoplasmic reticulum occurs mostly in those cells, which are involved in the metabolism of lipids (including steroids) and glycogen. The smooth endoplasmic reticulum is general found in adipose cells, interstitial cells, glycogen storing cells of the liver, conduction fibres of heart, spermatocytes and leucocytes. The muscle cells are also rich in smooth type of endoplasmic reticulum and here it is known as sarcoplasmic reticulum. In the pigmented retinal cells it exists in the form of tightly packed vesicles and tubes known as myeloid bodies.
Glycosomes. Although the SER forms a continuous system with RER, it has different morphology. For example, in liver cells it consists of a tubular network that pervades major portion of the cytoplasmic matrix. These fine tubules are present in regions rich in glycogen and can be observed as dense particles, called glycosomes, in the matrix. Glycosomes measure 50 to 200 mm in diameter and contain glycogen along with enzymes involved in the synthesis of glycogen (Rybicka, 1981). Many glycosomes attached to the membranes of SER have been observed by electron microscopy in the liver and conduction fibre of heart.
2. Granular of Rough Endoplasmic Reticulum
The granular or rough type of endoplasmic reticulum possesses rough walls because the ribosomes remain attached with its membranes. Ribosomes play a vital role in the process of protein synthesis. The granular or rough type of endoplasmic reticulum is found abundantly in those cells which are active in protein sysnthesis such as pancreatic cells, plasma cells, goblet cells, and liver cells. The granular type of endoplasmic reticulum takes basiophilic stain due to its RNA content of ribosomes. The region of the matrix containing granular type of endoplasmic reticulum takes basiophilic stain and is names as ergastoplasm, basiophilic bodies, chromophilic substances or Nissl bodies by early cytologists. In RER, ribosomes are often present as polysomes held together by mRNA and are arranged in typical, "rosettes" of spirals. RER contains two transmembrane glycoproteins (called ribophorins I and II of 65,000 and 64,000 dalton MW, respectively), to which are attached the ribosomes by their 60S subunits.
Isolation and chemical composition
The membranes of the endoplasmic reticulum can be isolated by subjecting homogenized tissues to differential centrifugation. Electron microscopy of such ER preparations reveals that the membranes disrupt to form closed vesicles (~100 nm diameter) of either a rough or a smooth form. These membranous entities were coined the term "microsomes" by Claude in 1940, and the relationship between microsomes and the elements of endoplasmic reticulum in the intact cell was established by Palade and Siekevitz 1956.
Microsomes derived from rough ER are studded with and are called rough or granular microsomes. The ribosomes are always found on the outside surface, the interior beings biochemical equivalent to the luminal space of the ER. Homogenate also contains smooth or agranular micro-somes which lack attached ribosomes. They may be derived in part from smooth portion of the ER and in part from fragments of plasma membrane, Golgi apparatus, endosomes and mitochondria. Thus, while rough microsomes can be equated with rough portions of ER, the origin of smooth microsomes cannot be so easily assigned. However, since the hepatocytes of liver contain exceedingly large quantities of smooth ER, therefore, most of the smooth microsomes in liver homogenates are derived from smooth ER (see Alberts et al., 1989).
Enzymes of the ER membranes
The membranes of the endoplasmic reticulum are found to contain many kinds of enzymes which are needed for various important synthetic activities. Some of the most common enzymes are found to have different transverse distribution in the ER membranes (Table 6-1). The most important enzymes are the stearases, NADH-cytochrome C reductase, NADH diaphorase, glucose-6-phosphotase and Mg++ activated ATPase. Certain enzymes of the endoplasmic reticulum such as nucleotide diphosphate are involved in the biosynthesis of phospholipids, ascorbic acid, glucuronide, steroids and hexose metabolism. The enzymes of the endoplasmic reticulum perform the following important functions :
1. Synthesis of glycerides, e.g., triglycerides, phospholipids, glycolipids and plasmalogens.
2. Metabolism of plasmalogens.
3. Sythesis of fatty acids.
4. Biosynthesis of the steroids, e.g., cholesterol biosynthesis, steroid hydrogenation of unsaturated bonds.
5. NADPH2+O2- requiring steroid transformations : Aromatization and hydroxylation.
6. NADPH2+O2-requireing steroid transformations : Aromatization hydroxylation's side-chain oxidation, thio-ether oxidations, desulphuration.
7. L-ascorbic acid metabolism.
8. UDP-glucose dephosphorylation.
9. Ary1- and steroid sulphatase.
Origin of Endoplasmic reticulum
The exact process of the origin of endoplasmic reticulum is still unknown. But because membranes of ER resemble with the nuclear membrane and plasma membrane and also at the telophase stage the ER membranes are found the nuclear envelope. Therefore, it is normally assumed that the ER has originated by evagination of the nuclear membranes. Teikevitz and Palade (1960) have reported that the granular type of ER has originated first and later it synthesizes the agranular or smooth type of endoplasmic reticulum.
The synthesis of membranes of ER is found to proceed in the following direction : RER®SER. In face, membrane biogenesis is a multi-step process involving, first, the synthesis of a basic membrane of lipid and intrinsic proteins and thereafter the addition of other constituents such as enzymes, specific sugars, or lipids. The process by which a membrane is modified chemically and structurally is called membrane differentiation. The insertion of proteins into ER membranes occurs at the level of RER. Most of these proteins are formed on membrane-bound ribosomes. However, some of these are synthesized by free ribosomes in the cytosol (cytoplasmic matrix) and then are inserted into the membrane. For example, the enzyme NAD-cytochrome-b5-reductase is synthesized in the cytosol (cytoplasmic matrix) and then becomes incorporated in various parts of the endomembrane system (i.e., RER, SER and Golgi apparatus) and in the outer mitochondrial membrane (Borghese and Gaetani, 1980).
Function of Endoplasmic reticulum
The endoplasmic reticulum acts as secretory, storage, circulatory and nervous system for the cell. performs following important functions :
A. Common Functions of Granular and Agranular Endoplasmic Reticulum
1. The endoplasmic reticulum provides and ultrastructural skeletal framework to the cell and gives mechanical support to the colloidal cytoplasmic matrix.
2. The exchange of molecules by the process of osmosis, diffusion and active transport occurs through the membranes of endoplasmic reticulum. Like plasma membrane, the ER membrane has permeases and carries.
3. The endoplasmic membranes contain many enzymes which perform various synthetic and metabolic activities. Further the endoplasmic reticulum provides increase surface for various enzymatic reactions.
4. The endoplasmic reticulum acts as an intracellular circulatory or transporting system. Various secretory products of granular endoplasmic reticulum are transported to various organelles as follows : Granular ER®agranular ER®Golgi membrane®lysosomes, transport vesicles or secretory granules. Membrane flow many also be an important mechanism for carrying particles, molecules and ions into and out of the cells. Export of RNA and nucleoproteins from nucleus to cytoplasm may also occur by this type of flow (see De Robertis and De Robertis, Jr., 1987).
5. The ER membranes are found to conduct intra-cellular impulses. For example, the sarcoplasmic reticulum transmits impulses from the surface membrane into the deep region of the muscle fibres.
6. The ER membranes form the new nuclear envelope after each nuclear division.
7. The sarcoplasmic reticulum plays a role in releasing calcium when the muscle is stimulated and actively transporting calcium back into the sarcoplasmic reticulum when the stimulation stops and the muscle must be relaxed.
B. Functions of Smooth Endoplasmicreticulum
Smooth ER performs the following functions of the cell :
1. Synthesis of lipids. SER perform synthesis of lipids (e.g., phospholipids, cholesterol, etc.) and lipoproteins. Studies with radioactive precursors have indicated that the newly synthesized phospholipids are rapidly transferred to other cellular membranes by the help of specific cytosolic enzymes, called phospholipids exchange proteins.
2. Glycogenolysis and blood glucose homeostasis. This process of glycogen synthesis (glycogenesis) occurs in the cytosol (in glycosomes). The enzyme UDPG-glycogen transferase, which is directly involved in the synthesis of glycogen by addition of uridine diphosphate glucose (UDPG) to primer glycogen is bound to the glycogen particles or glycosomes.
SER is found related to glycogenolysis or breakdown of glycogen. An enzyme, called glucose-6-phosphatase (a marker enzyme) exists as an integral protein of the membrane of SER (e.g., liver cell). Generally, this enzyme acts as a glycogenic phosphorhydrolase that catalyzes the release of free glucose molecule in the lumen of SER from its phosphorylated form in liver. Thus, this process operates to maintain homeostatic levels of glucose in the blood for the maintenance of functions of red blood cells and nerve tissues.
3. Sterol metabolism. The SER contains several key enzymes that catalyze the synthesis of cholesterol which is also a precursor substance for the biosynthesis of two types of compounds- the steroid hormones and bile acids :
(i) Cholesterol biosynthesis. The cholesterol is synthesized from the acetate and its entire biosynthetic pathway involve about 20 steps, each step catalyzed by an enzyme. Out of these twenty enzymes, eleven enzymes are bounded to SER membranes, rest nine enzymes are the soluble enzymes located in the cytosol and mitochondria. Examples of SER-bound enzyme include HMG-Co A reductase and squalene synthetase (see Thorpe, 1984).
(ii) Bile acid synthesis. The biosynthesis of the bile acids represents a very complex pattern of enzymes and products. Enzymes involved in the biosynthetic pathway of bile acids are hydroxylases, mono-oxygenases, dehydrogenases, isomerases and reductases. For example, by the help of the enzyme cholesterol 7a-hydroxylase, the cholesterol is first converted into 7a-hydroxyl cholesterol, which is then converted into bile acids by the help of hydroxylase enzymes. The latter reaction requires NADPH and molecular oxygen and depends on the enzymes of Electron transport chains of SER such as cytochrome P-450 and NADPH-cytochrome-c reductase .
(iii) Steroid hormone biosynthesis. Steroid hormones are synthesized in the cells of various organs such as the cortex of adrenal gland, the ovaries, the testes and the placenta. For example, cholesterol is the precursor for both types of sex hormones-estrogen and testosterone-made in the reproductive tissues, and the adrenocorticoids (e.g., corticosterone, aldosterone and cortisol) formed in the adrenal glands. Many enzymes (e.g., dehydrogenase,s isomerases and hydroxylases) are involved in the biosynthetic pathway of steroid hormones, some of which are located in SER membranes and some occur in the mitochondria
4. Detoxification. Protectively, the ER chemically modifies xenobiotics (toxic materials of both endogenous and exogenous origin), making them more hydrophilic, hence, more readily excreted. Among these materials are drugs, aspirin (acetyl-salicylic-acid), insecticides, anaesthetics, petroleum products, pollutant and carcinogens (i.e., inducers of cancer ; e.g., 3-4-benzophrene and 3-methyl cholantherene).
The enzymes involved in the detoxification of aromatic hydrocarbonds are aryhydraoxylases. It is now know that benzophyrene (found in charcoal-broiled meat) is not carcinogenic, but under the action of aryl hydroxylase enzyme in the liver, it is converted into 5,6-epoxide, which is a powerful carcinogen (see De Robertis and De Robertis, Jr., 1987)
A wide variety of drugs (e.g., Phenobarbital), when administrated to animals, they bring about the proliferation of the ER membranes (first RER and then SER) and /or enhanced activity of enzymes related to detoxification (Thorpoe, 1984).
C. Functions of Rough Endoplasmic Reticulum
The major function of the rough ER is the synthesis of protein. It has long been assumed that proteins destined for secretion (i.e., export) from the cell or proteins to be used in the synthesis of cellular membranes are synthesized on rough DR-bound ribosomes, while cytoplasmic proteins are translated for the most part on free ribosomes. In fact, the array of the rough endoplasmic reticulum provides extensive surface area for the association of metabolically active enzymes, amino acids and ribosomes. There is more efficient functioning of these materials to synthesize proteins when oriented on a membrane surface than when they are simply in solution, mainly because chemical combinations between molecules can be accomplished in specific geometric patterns.
The membrane-bound ribosomes are attached with specific binding sites or receptors of rough ER membrane by their large 60S subunit, with small or 40S subunit sitting on top like a cap. These receptors are membrane proteins which extend well into and possibly through the lipid bilayer. The receptor proteins with bound ribosomes can float laterally like other membrane proteins and may facilitate formation of the polysome and probably translation which requires that mRNA and ribosome move with respect to each other.
Further, the secretory proteins, instead of passing into the cytoplasm, appear to pass instead into the cisternae of the rough ER and are, thus, protected from protease enzymes of cytoplasm. It is calculated that about 40 amino acid residues long segment at the - COOH end of the nascent protein remains protected inside the tunnel of 'free' or 'bond' ribosomes and rest of the chain, with-NH2 end, is protected by the lumen of RER. The passage of nascent polypeptide chain into the ER cisterna take place during translation leaving only a small segment exposed to the cytoplasm at any one time.
Protein glycosylation. The covalent addition of sugars to the secretory proteins (i.e., glycosylation) is one of the major biosynthetic functions of rough ER. Most of the proteins that are isolated in the lumen of RER before being transported to the Golgi apparatus, lysosomes, plasma membrane or extracellular space, are glycoproteins (A notable exception is albumin). In contrast, very few proteins in the cytosol (Cytoplasmic matrix) are glycosylated and those that carry them have a different sugar modification.
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