# Endoplasmic Reticulum (ER): Structure and Functions of Rough and Smooth ER

> Endoplasmic reticulum (ER) is a continuous and dynamic membrane system present in the cytoplasm of eukaryotic cells. It is made up of interconnected...

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Author: Sourav Pan
Last updated: September 12, 2026

![Endoplasmic Reticulum (ER): Structure and Functions of Rough and Smooth ER](https://biologynotesonline.com/wp-content/uploads/2024/04/Structure-of-the-Endoplasmic-Reticulum-Rough-and-Smooth-ER.webp)

Endoplasmic reticulum (ER) is a continuous and dynamic membrane system present in the cytoplasm of eukaryotic cells. It is made up of interconnected membranous tubules and flattened sacs called cisternae, enclosing an internal space known as the ER lumen. The membrane network is spread throughout the cytoplasm. Its shape and arrangement can also change within the cell.

The ER occurs in two main regions i.e. rough endoplasmic reticulum (RER) and smooth endoplasmic reticulum (SER). These are regions of the same continuous network and are not two different organelles. Rough ER contains ribosomes attached on its cytoplasmic surface, whereas the smooth ER lacks these attached ribosomes. Both remain connected as a part of the same ER membrane system. The ER membrane is also continuous with the outer membrane of the nuclear envelope.

ER is one of the major components of the endomembrane system of eukaryotic cell. This system includes the nuclear envelope, ER, Golgi apparatus, transport vesicles and other membrane-bound compartments. They work together in the movement and distribution of proteins, lipids and membrane materials inside the cell. Transport vesicles provide the connection between ER, Golgi apparatus and other compartments of this system.

### Cellular Location and Occurrence of Endoplasmic Reticulum

- Endoplasmic reticulum (ER) is a membrane-bound organelle housed in the cytoplasm of [eukaryotic cells](https://biologynotesonline.com/eukaryotic-cell/). It is found in both plant and animal cells. A true membrane-bound ER is not found in prokaryotic cells.

- The ER is a continuous network of membranous sacs and tubules spread within the cell cytoplasm. It lies around the nuclear region and also extends into other portions of the cell. The membrane is continuous with the outer membrane of the nuclear envelope, giving a connection between the nucleus and the cell cytoplasm.

- The amount of ER found in a cell varies depending on the function of the cell and its metabolic activity. Therefore, some cells have a highly developed endoplasmic reticulum. In others, it is less prominent.

- Rough Endoplasmic Reticulum (RER)- It is found in large amounts in cells which are actively producing and secreting proteins. Pancreatic exocrine cells, for example, possess extensive rough ER because large quantities of digestive enzymes are produced by these cells. Antibody-secreting plasma cells also have well-developed rough ER.

- Smooth Endoplasmic Reticulum (SER)- The smooth ER is abundant mainly in cells involved in lipid and steroid metabolism. Large amounts are found in steroid-producing cells of the testis and ovary. In hepatocytes (liver cells), it is also well developed, associated with metabolism and detoxification of lipid-soluble compounds.

- Muscle cells- In these cells, a specialized smooth endoplasmic reticulum is present, known as the sarcoplasmic reticulum (SR). It forms an extensive membrane system. This is associated with storing and releasing calcium ions during muscle contraction.

- Plant cells- The ER is found distributed throughout the cytoplasm and connected with the nuclear envelope. Both rough and smooth regions can occur depending on the activity of the plant cell. It forms part of the continuous membranous system within the cell cytosol.

## Structure and Organization of the ER

The endoplasmic reticulum (ER) is organized as a continuous membrane system formed of flattened sacs, sheets and interconnected tubules. The internal space of this membrane network is called the ER lumen.

![Continuous endoplasmic reticulum network showing rough ER sheets with ribosomes, smooth ER tubules, the ER lumen, and continuity with the outer nuclear membrane.](https://biologynotesonline.com/wp-content/uploads/2024/04/Structure-of-the-Endoplasmic-Reticulum-Rough-and-Smooth-ER-1024x768.webp)Continuous endoplasmic reticulum network showing rough ER sheets with ribosomes, smooth ER tubules, the ER lumen, and continuity with the outer nuclear membrane.

- Membrane- The ER membrane extends through the cytoplasm as a continuous network. Different regions may have different shape. The outer nuclear membrane is also continuous with the ER.

- Lipid bilayer- The ER membrane is made up of a lipid bilayer with different membrane proteins. It separates the ER lumen from the surrounding cytosol.

- Lumen- The space enclosed within the ER membrane is called the ER lumen or cisternal space. This space continues through the sheets and tubules. It is also continuous with the space present between the two nuclear membranes.

- Cisternae- These are flattened membrane-bound sacs of the ER. Several cisternae may lie close to each other. Rough ER is commonly arranged in this form.

- Tubules- These are narrow and curved membrane structures. The tubules branch and join with one another at different points, forming an interconnected network in the cytoplasm.

- Rough ER- Ribosomes are attached on the cytosolic surface of rough ER. Because of these ribosomes, the membrane appears rough. It is commonly present in the form of flattened sheets or cisternae.

- Smooth ER- Smooth ER does not have ribosomes attached to its surface. It is mainly formed of branching tubules. Rough and smooth regions remain continuous with each other.

- Nuclear envelope- The outer membrane of the [nuclear envelope](https://biologynotesonline.com/nucleus-structure-and-functions/) is continuous with the ER membrane. The perinuclear space also continues with the lumen of ER.

- Junctions- ER tubules meet at different points and form junctions. Three-way junctions are commonly present in the tubular network.

- Arrangement- The amount of sheets and tubules is not the same in every cell. Some cells have more flattened cisternae, while others contain a more extensive tubular ER.

## Rough and Smooth Endoplasmic Reticulum

The endoplasmic reticulum (ER) is made up of two regions known as the rough endoplasmic reticulum and smooth endoplasmic reticulum. Rough ER has ribosomes attached to the surface membrane, while smooth ER lacks ribosomal attachment. Both are parts of the same ER system but have different structural appearance and major functions.

### Rough Endoplasmic Reticulum (RER)

- The rough endoplasmic reticulum (RER) is covered by [ribosomes](https://biologynotesonline.com/ribosomes-structure-and-functions/) around its cytosolic surface membrane, making a rough bumpy appearance. These ribosomes are responsible for translation, not the ER membrane itself.

- Rough ER mainly appears as flattened membrane sheets or sacs. These flattened interconnected sacs are called cisternae. In many cells, they lie close to one another forming stacks, rather than the more tubular arrangement that characterizes smooth ER.

- It is attached and continuous with the outer membrane of the nuclear envelope. The internal space also continues with the space between the nuclear membranes. In this way, the rough ER extends out from the nuclear region into the cytoplasm.

- Ribosomes do not remain permanently attached to the rough ER. During synthesis of particular proteins, a ribosome becomes associated with the ER membrane and the growing polypeptide is directed into or across the ER. After translation is completed, the ribosome may leave the membrane again.

- The assembling of proteins is accomplished by the ribosomes attached to rough ER. The ER therefore provides the membrane system where many newly synthesized proteins enter and begin their processing, but the actual formation of the polypeptide chain is carried out by ribosomes.

- Rough ER is found in high amounts in cells where proteins are actively produced for secretion. Pancreatic secretory cells have extensive rough ER. Plasma cells producing antibodies also contain a highly developed rough ER.

### Smooth Endoplasmic Reticulum (SER)

- The smooth endoplasmic reticulum (SER) is smooth due to a lack of attached surface ribosomes. It forms a continuous part of the ER membrane system and may extend from regions of rough ER.

- Unlike the broad cisternae of rough ER, smooth ER is mainly tubular. The tubules branch and connect with one another through the cytoplasm, forming an irregular membrane network.

- Smooth ER is not present in the same amount in every cell. In cells where lipid metabolism, detoxification or calcium handling are high, its network can be much more developed.

- Its major association is with lipid metabolism and formation of new membrane lipids. Cells actively involved in steroid and lipid metabolism therefore contain a large amount of smooth ER.

- Smooth ER is also associated with metabolism and detoxification of drugs and other foreign compounds. This type of ER is particularly developed in liver cells (hepatocytes).

- Another role of smooth ER is the handling and storage of Ca²⁺. In muscle cells, a specialized smooth ER forms the sarcoplasmic reticulum, which takes up and releases calcium during muscle activity.

### Rough ER vs Smooth ER

FeatureRough ER (RER)Smooth ER (SER)RibosomesRibosomes are attached to its cytosolic surface. The attachment is functional and temporary.Surface ribosomes are absent.Typical structureMostly flattened sheets or cisternae, often present in stacks.Mostly branched and interconnected tubules.Major roleMainly associated with synthesis and handling of proteins meant for secretion or membranes. Ribosomes carry out translation.Mainly associated with lipid metabolism, detoxification and calcium handling.Commonly developed inPancreatic secretory cells and antibody-producing plasma cells.Hepatocytes, steroid-producing cells and muscle cells (specialized as sarcoplasmic reticulum).

## Functions of the Endoplasmic Reticulum

The endoplasmic reticulum (ER) performs different functions related to protein and lipid synthesis, transport, detoxification and calcium storage. Rough ER is mainly associated with proteins, while smooth ER carries out several lipid-related and metabolic functions.

- Protein synthesis- Rough ER is associated with synthesis of secretory and membrane proteins. [Translation](https://biologynotesonline.com/protein-synthesis-translation-definition-steps-sites-machinery/) is carried out by the ribosomes attached on its surface.

- Protein folding- Newly formed polypeptides enter the ER lumen and are folded into their proper form. ER chaperone proteins help during this process.

- Protein modification- Some proteins undergo modification inside the ER. These include N-linked glycosylation, formation of disulfide bonds and removal of signal sequences.

- Quality control- Improperly folded proteins are retained within the ER. They may be refolded or removed by ER-associated degradation (ERAD).

- Lipid synthesis- Smooth ER is an important site for the synthesis of phospholipids and other membrane lipids.

- Membrane formation- Lipids and membrane proteins produced in the ER are used for the formation and growth of cellular membranes.

- Steroid synthesis- Smooth ER takes part in the synthesis of steroid hormones. It is therefore highly developed in steroid-producing cells.

- Detoxification- Smooth ER of liver cells helps in the metabolism of drugs and different lipid-soluble compounds. Cytochrome P450 enzymes are mainly involved in this process.

- Calcium storage- ER stores Ca²⁺ inside its lumen and releases it when required. In muscle cells, this function is carried out by the sarcoplasmic reticulum (SR).

- Transport- Proteins and lipids formed in the ER are packed into transport vesicles and carried to the [Golgi apparatus](https://biologynotesonline.com/golgi-apparatus/) for further processing.

## Biogenesis of Endoplasmic Reticulum (ER)

The endoplasmic reticulum (ER) is mainly formed by growth and remodelling of the already existing ER membrane. It is not produced every time as a completely new organelle. New membrane lipids and proteins are continuously added to it, so the ER can expand according to the requirement of the cell.

![Endoplasmic reticulum biogenesis showing growth of pre-existing ER through lipid and membrane-protein addition, formation of rough ER sheets and smooth tubules, continuity with the nuclear envelope, and inheritance during cell division.](https://biologynotesonline.com/wp-content/uploads/2024/04/Biogenesis-of-the-Endoplasmic-Reticulum-ER-1024x427.png)ER biogenesis occurs mainly through expansion and remodeling of pre-existing ER, with continuous addition of membrane lipids and proteins, dynamic organization into sheets and tubules, and inheritance of the membrane network by daughter cells.

- Growth of pre-existing ER- The existing ER acts as the membrane framework for its further growth. During cell growth, additional membrane material is incorporated into this network. Thus, ER biogenesis involves expansion, branching and rearrangement of a continuous membrane system rather than formation of separate membrane sacs from the cytoplasm.

- Synthesis of membrane lipids- The ER is a major site where cellular membrane lipids are produced. New phospholipids are synthesized mainly on the cytosolic side of the ER membrane from lipid precursors. They become inserted into the existing bilayer and are redistributed between the two membrane leaflets. In this way the membrane surface increases.

- Addition of membrane proteins- Newly made ER membrane proteins are inserted into the growing membrane. For many proteins, the nascent polypeptide is recognized by the signal recognition particle (SRP) and the ribosome is brought to ER, where the protein enters or becomes inserted through the Sec61 translocon. Some membrane proteins use other insertion pathways. The membrane therefore receives both its lipid and protein components during its growth.

- Formation of rough ER- Ribosomes become associated with regions of ER when proteins carrying appropriate ER-targeting signals are being synthesized. Such ribosome-bearing regions appear as rough endoplasmic reticulum (RER). The ribosomes are not permanent structural components of the membrane. Rough and smooth ER are different domains of the same continuous ER system.

- Formation of sheets and tubules- As ER membrane grows, it is arranged into flattened cisternae and interconnected tubules. Membrane-shaping proteins help to produce highly curved tubules and the edges of ER sheets, while membrane fusion joins the tubules and maintains the continuous network. The proportion of sheets and tubules can change considerably between different cells and according to cellular activity.

- Nuclear envelope continuity- The ER membrane is continuous with the outer nuclear membrane, and their internal spaces are also connected. Proteins and lipids produced in ER can therefore move into nuclear-envelope membranes through this continuous membrane system. During the cell cycle the ER and nuclear envelope undergo extensive rearrangement, particularly in cells having open mitosis.

- ER inheritance- During cell division, pre-existing ER is distributed between the forming daughter cells. The network undergoes major structural changes, but ER membrane is maintained and then expanded again in daughter cells by synthesis of new lipids and proteins. This inheritance provides the starting ER from which the new cellular ER network grows.

## Mechanisms of ER

### Protein Targeting and Translocation by ER

Protein targeting to the endoplasmic reticulum (ER) directs newly forming secretory and membrane proteins from cytosolic ribosomes to the ER membrane. In most cases it takes place along with translation, followed by transfer of the growing polypeptide through the Sec61 translocon.

![SRP directs a ribosome with an ER signal sequence to the SRP receptor and Sec61 translocon, allowing the growing protein to enter the ER lumen or membrane.](https://biologynotesonline.com/wp-content/uploads/2024/04/Protein-Targeting-and-Translocation-into-the-Endoplasmic-Reticulum-1024x768.webp)SRP directs a ribosome with an ER signal sequence to the SRP receptor and Sec61 translocon, allowing the growing protein to enter the ER lumen or membrane.

- The process begins when translation of mRNA starts on a free ribosome in the cytosol. At this stage, the ribosome is not permanently attached to the rough ER.

- As translation proceeds, an ER signal sequence of the growing polypeptide comes out from the ribosome. It generally contains a hydrophobic region which acts as the targeting signal for ER.

- The exposed signal sequence is recognized by the signal recognition particle (SRP). SRP binds with the signal sequence and also with the ribosome carrying the growing polypeptide chain.

- After the binding of SRP, further translation is temporarily slowed or paused. The complete SRP-ribosome-growing polypeptide complex is then carried towards the ER membrane.

- At the ER membrane, SRP binds with its specific SRP receptor. In this step, the ribosome and growing polypeptide are brought close to the protein translocation machinery present in the ER membrane.

- The ribosome is now transferred to the Sec61 translocon, which forms the protein-conducting channel across the ER membrane. SRP is released from the complex and can be used again.

- Translation starts again. As amino acids are continuously added by the ribosome, the growing polypeptide is passed directly through the Sec61 channel into the ER lumen. This is referred to as co-translational translocation.

- During this process, the signal sequence enters the translocon. For many soluble secretory proteins, it is removed by signal peptidase present on the ER side of the membrane.

- The remaining polypeptide continues to move into the ER lumen as its synthesis proceeds. Once translation is completed, the newly synthesized protein is released into the lumen, where folding and initial processing can take place.

- In case of membrane proteins, particular hydrophobic transmembrane sequences are not completely passed into the lumen. They leave the Sec61 channel laterally and become inserted into the ER membrane.

- Not all ER proteins enter by the co-translational process. Some proteins are completely synthesized first and then transported to the ER by post-translational translocation, involving cytosolic chaperones and additional ER translocation proteins.

### Protein Folding and Modification by ER

After entering the ER lumen, newly synthesized polypeptide undergoes folding and different modifications before it is allowed to move further in the secretory pathway. Chaperone proteins, glycosylation enzymes and folding enzymes are involved in this process.

- As the growing polypeptide enters into ER lumen, folding starts. The exposed portions of the chain are bound by ER chaperones such as BiP, which helps the protein to fold and prevents unwanted aggregation.

- During entry into ER, the signal peptide of many proteins is cut off by signal peptidase. The remaining polypeptide is then further folded inside the lumen.

- Many proteins are modified by N-linked glycosylation. In this step, a preformed oligosaccharide is transferred to a suitable asparagine (Asn) residue of the growing protein by oligosaccharyl transferase (OST). This may occur while the protein is still being translocated.

- After addition of the oligosaccharide, some of its glucose residues are removed. The partly trimmed glycoprotein can now bind with calnexin or calreticulin. These chaperones hold the incompletely folded protein and help in getting its proper form.

- Disulfide bonds (S-S bonds) are also formed between cysteine residues. The reaction is helped by protein disulfide isomerase (PDI). Incorrect disulfide bonds can also be broken and rearranged by PDI until a suitable bond arrangement is produced.

- Folding continues with the help of ER chaperones and folding enzymes. Some proteins also join with other polypeptide chains to form their proper multimeric structure. The ER lumen provides an oxidizing condition which supports this folding process.

- If a glycoprotein is still not folded correctly, it may be returned again to the calnexin-calreticulin cycle. A glucose is added back to the oligosaccharide and another round of folding takes place.

- Properly folded proteins are released from these chaperones. They can then move towards ER exit sites for transport to the Golgi apparatus.

- Proteins which fail to obtain their proper structure are retained in the ER. Some are given another chance for folding, while persistently misfolded proteins are sent out to the cytosol for ER-associated degradation (ERAD) and degraded by proteasomes.

![Newly synthesized ER glycoproteins undergo chaperone-assisted folding and calnexin-calreticulin quality control, with correctly folded proteins exported and persistent misfolded proteins sent to ERAD and the proteasome.](https://biologynotesonline.com/wp-content/uploads/2024/04/ER-Protein-Folding-Quality-Control-and-ERAD-1024x768.webp)Newly synthesized ER glycoproteins undergo chaperone-assisted folding and calnexin-calreticulin quality control, with correctly folded proteins exported and persistent misfolded proteins sent to ERAD and the proteasome.

### Protein Quality Control by ER

Protein quality control in the endoplasmic reticulum (ER) checks newly synthesized proteins for their correct folding. Properly folded proteins are allowed to move further, while unfolded or wrongly folded proteins are retained in ER.

- Newly formed proteins entering the ER are first bound by molecular chaperones such as BiP. These chaperones help the polypeptide during folding and also prevent its aggregation.

- In case of glycoproteins, the attached N-linked oligosaccharide also takes part in quality control. Glucose residues are removed from the oligosaccharide and a monoglucosylated form is produced.

- The monoglucosylated glycoprotein binds with calnexin or calreticulin. During this process, the protein is kept inside the ER and another chance for proper folding is provided. ERp57 also assists in formation and rearrangement of disulfide bonds.

- After folding, the last glucose is removed by glucosidase II and the protein is released from calnexin or calreticulin. Its folded condition is then checked.

- If the protein is still not folded correctly, UGGT (UDP-glucose glucosyltransferase) recognizes the incompletely folded glycoprotein. A glucose residue is added again and the protein goes back to the calnexin-calreticulin cycle for another folding attempt.

- A protein that obtains its proper native structure is released from the ER quality-control machinery. It can then leave the ER and move towards the Golgi apparatus.

- Proteins which repeatedly fail to fold are retained and selected for ER-associated degradation (ERAD). Mannose trimming of N-linked glycans can take part in directing persistently misfolded glycoproteins towards this pathway.

- During ERAD, the defective protein is moved from the ER towards the cytosolic side. This process is generally referred to as retrotranslocation.

- The misfolded protein is then tagged with ubiquitin and finally degraded by the cytosolic 26S proteasome.

### Lipid Synthesis and Membrane Biogenesis by ER

The endoplasmic reticulum (ER) is a major site for synthesis of membrane lipids. Phospholipids are formed in ER membrane and the newly formed lipids become part of the same bilayer during membrane growth.

![Phospholipids are synthesized on the cytosolic side of the ER, redistributed between membrane leaflets, and combined with membrane proteins during ER membrane growth.](https://biologynotesonline.com/wp-content/uploads/2024/04/Lipid-Synthesis-and-Membrane-Biogenesis-in-the-Endoplasmic-Reticulum-1024x512.webp)Phospholipids are synthesized on the cytosolic side of the ER, redistributed between membrane leaflets, and combined with membrane proteins during ER membrane growth.

- The process starts on the cytosolic side of ER membrane. Enzymes required for phospholipid synthesis are present in the membrane with their active sites facing towards cytosol.

- Fatty acyl-CoA and glycerol-3-phosphate are used for the formation of phosphatidic acid. Two fatty acids are added one after another. The phosphatidic acid formed remains inserted in the membrane.

- Phosphatidic acid is further used for making different phospholipids. Phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI) are produced through ER-associated pathways.

- Newly synthesized phospholipids are first added mainly into the cytosolic leaflet of ER membrane. This increases the lipid content of one side of the bilayer.

- Some of these phospholipids are then moved across to the opposite leaflet. Lipid scrambling between the two leaflets allows both sides of ER membrane to increase during membrane formation.

- ER also carries out synthesis of cholesterol and the early steps of sphingolipid formation. Ceramide is formed in ER and is later transferred to Golgi apparatus for further modification.

- At the same time, newly synthesized membrane proteins are inserted into ER membrane. Lipids and membrane proteins are therefore added to the growing ER membrane during its biogenesis.

- Portions of ER membrane containing proteins and lipids are transported to the Golgi apparatus through the secretory pathway. From there, these membrane components can be distributed to other parts of the endomembrane system and plasma membrane.

- Lipids produced in ER can also be supplied to some organelles without passing through Golgi. Transfer of ER-derived lipids occurs to organelles such as mitochondria, including through close membrane contact regions.

### Calcium Storage and Signaling by ER

Calcium storage and signaling by the endoplasmic reticulum (ER) is based on the uptake, storage and release of Ca²⁺. The concentration of calcium is kept high inside the ER lumen compared to the cytosol.

![ER calcium signaling showing SERCA-mediated uptake, IP3 receptor and ryanodine receptor release, and STIM1–Orai1 store-operated calcium entry after ER calcium depletion.](https://biologynotesonline.com/wp-content/uploads/2024/04/Endoplasmic-Reticulum-Calcium-Storage-and-SOCE-Signaling-980x1024.webp)ER calcium signaling showing SERCA-mediated uptake, IP3 receptor and ryanodine receptor release, and STIM1–Orai1 store-operated calcium entry after ER calcium depletion.

- Ca²⁺ from the cytosol is first transported into the ER lumen by sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA). ATP is utilized in this step.

- Inside the ER, calcium is stored in high amount and some of it remains bound with calcium-binding proteins such as calreticulin. In muscle sarcoplasmic reticulum, calsequestrin performs this function.

- When the cell receives a suitable stimulus, phospholipase C (PLC) can be activated and inositol 1,4,5-trisphosphate (IP₃) is formed. IP₃ then moves through the cytosol.

- The IP₃ binds to IP₃ receptor (IP₃R) present on the ER membrane. The channel opens and Ca²⁺ stored inside ER is released into cytosol.

- Calcium can also come out through ryanodine receptor (RyR). These calcium channels are especially important in excitable cells and muscle sarcoplasmic reticulum.

- After release, the amount of Ca²⁺ in cytosol rises for a short period. This calcium takes part in cellular activities such as secretion, muscle contraction and activation of calcium-sensitive proteins.

- During this process, calcium present inside the ER becomes lower. STIM1, present in ER membrane, detects the decrease in luminal Ca²⁺.

- Activated STIM1 then moves towards ER-plasma membrane contact regions and interacts with Orai1 channels present in plasma membrane. Orai1 channels are opened.

- Extracellular Ca²⁺ enters the cytosol through these Orai channels. This process is referred to as store-operated calcium entry (SOCE).

- After the calcium signal, SERCA again transports Ca²⁺ from cytosol into the ER lumen. The ER calcium store is filled again and cytosolic calcium is brought down towards its resting level.

### Detoxification and Carbohydrate Metabolism by ER

The smooth endoplasmic reticulum (SER) takes part in detoxification of drugs and different foreign compounds, mainly in liver cells. ER is also involved in carbohydrate metabolism where glucose-6-phosphate is converted into free glucose.

#### Detoxification by ER

- Drugs and other lipid-soluble foreign compounds enter into the liver cells. Enzymes involved in their metabolism are present in the membrane of smooth ER.

- The compound first binds with cytochrome P450 (CYP) enzyme. These enzymes are mainly associated with ER membrane.

- Electrons required for the reaction are supplied from NADPH through NADPH-cytochrome P450 reductase. Oxygen is also required during this process.

- The compound is then oxidized by cytochrome P450. A functional group may be added or exposed and the original compound is changed into a more polar metabolite.

- Some of these products are further modified by ER enzymes. During glucuronidation, UDP-glucuronosyltransferase (UGT) adds glucuronic acid to the compound.

- The modified compounds are then available for removal through the normal excretory routes of the body.

#### Carbohydrate Metabolism by ER

- During [glycogen breakdown](https://biologynotesonline.com/glycogenolysis-enzymes-steps-regulation-functions/), glucose residues are mainly released as glucose-1-phosphate. This is then converted into glucose-6-phosphate (G6P) by phosphoglucomutase.

- Glucose-6-phosphate formed in the cytosol is transported into the ER lumen. Glucose-6-phosphate transporter (G6PT) is involved in this step.

- Inside the ER lumen, glucose-6-phosphate is acted upon by glucose-6-phosphatase (G6Pase). The catalytic part of this enzyme faces towards the ER lumen.

- Glucose-6-phosphate is hydrolyzed to form free glucose and inorganic phosphate (Pi). The reaction is as follows-Glucose-6-phosphate + H₂O → Glucose + Pi

- After this reaction, glucose is transported out from ER. In liver cells, the free glucose can then be released into the blood.

## ER Trafficking and Organelle Communication

The endoplasmic reticulum (ER) communicates with Golgi apparatus and other cell organelles. Some materials are transported through membrane carriers, while at other places the ER comes very close to another membrane and forms contact sites.

![Endoplasmic reticulum communication showing COPII-dependent cargo transport through ERGIC to the Golgi alongside non-fused ER contact sites with mitochondria and the plasma membrane.](https://biologynotesonline.com/wp-content/uploads/2024/04/ER–Golgi-Transport-and-Endoplasmic-Reticulum-Membrane-Contact-Sites-1024x683.webp)Endoplasmic reticulum communication showing COPII-dependent cargo transport through ERGIC to the Golgi alongside non-fused ER contact sites with mitochondria and the plasma membrane.

### ER Exit Sites and Golgi Transport

- Proteins which are properly folded inside the ER are selected for transport. Some membrane proteins interact directly with the transport machinery, while soluble proteins can be selected through cargo receptors.

- These proteins collect at special regions of ER known as ER exit sites (ERES). COPII coat proteins are assembled at these regions.

- In this step, COPII helps in selection and export of the cargo from ER. Transport carriers are then formed from the ER membrane containing the selected proteins and lipids.

- After leaving the ER, the cargo is carried towards the ER-Golgi intermediate compartment (ERGIC) in many animal cells. The ERGIC is present between ER and Golgi and also takes part in sorting of transported materials.

- From ERGIC, the forward-moving cargo is transported towards the cis-Golgi. Some proteins and transport components are also returned back towards ER through retrograde transport.

- The transport can be represented as follows-ER → ER exit site → COPII-associated carrier → ERGIC → cis-Golgi

- The ER membrane is directly continuous with the outer nuclear membrane. This type of continuity is not present between ER and Golgi. ER and Golgi remain separate membrane compartments, and materials between them are carried by transport carriers and intermediate compartments.

### Membrane Contact Sites

- ER membrane also comes very close to membranes of mitochondria, plasma membrane, Golgi, endosomes, peroxisomes and other organelles. These closely placed membrane regions are known as membrane contact sites (MCSs). The membranes remain separate and are not fused together.

- At ER-mitochondria contact sites, lipids can be exchanged between the two organelles. Calcium released from ER can also be transferred efficiently towards [mitochondria](https://biologynotesonline.com/mitochondria/) at these regions.

- The ER also forms contact regions with the [plasma membrane](https://biologynotesonline.com/cell-membrane-plasma-membrane-structures-and-functions/). These sites are involved in calcium signaling and non-vesicular transfer of different lipids between ER and plasma membrane.

- Contact sites are also formed with endosomes and other membrane-bound organelles. Lipids, ions and cellular signals can be exchanged or controlled at these regions without normal vesicle transport.

- ER contact sites can also take part in positioning and division of some organelles, particularly mitochondria and endosomes.

## ER Dysfunctions and Disorders

The endoplasmic reticulum (ER) may become disturbed when unfolded proteins collect inside it, calcium balance changes or the normal lipid and redox conditions are affected. This condition is known as ER stress. Long-lasting ER stress has been linked with several metabolic and degenerative disorders.

![ER stress activates the IRE1, PERK, and ATF6 branches of the unfolded protein response to reduce folding stress and restore ER homeostasis, while unresolved stress can promote cell-death signaling.](https://biologynotesonline.com/wp-content/uploads/2024/04/ER-Stress-and-the-Unfolded-Protein-Response-1024x853.webp)The unfolded protein response coordinates three principal ER stress pathways—IRE1, PERK, and ATF6—to restore protein homeostasis, although persistent unresolved stress can shift signaling toward maladaptive outcomes.

- ER stress- Accumulation of unfolded or wrongly folded proteins produces stress within ER. Changes in calcium level, glucose availability, glycosylation and redox condition can also produce ER stress.

- UPR- The unfolded protein response (UPR) is activated during ER stress. It mainly works through IRE1, PERK and ATF6 pathways, reducing the protein-folding load and increasing the folding capacity of ER.

- Cell death- When ER stress continues for a longer period and normal condition cannot be restored, the UPR may change from an adaptive response towards cell-death signaling. [Apoptosis](https://biologynotesonline.com/intrinsic-pathway-of-apoptosis/) can occur in severely stressed cells.

- Neurodegeneration- Persistent protein misfolding and ER stress have been associated with neurodegenerative disorders. Abnormal ER stress responses are reported in diseases involving progressive loss of neurons.

- Diabetes- ER stress is linked with type 2 diabetes mellitus, where prolonged stress can affect insulin-producing pancreatic β-cells and metabolic regulation. Disturbed UPR and cell death may occur when the stress becomes chronic.

- Liver disease- The liver has a high activity of protein and lipid metabolism, and disturbance of ER function has been linked with fatty liver and other metabolic liver disorders. Lipid imbalance itself can also put stress on ER.

- Inflammation- Prolonged ER stress can activate inflammatory responses in the cell. Such altered ER signaling has been linked with different chronic inflammatory disorders.

- Atherosclerosis- ER stress has also been associated with atherosclerosis. Prolonged stress and apoptosis of cells present within the arterial lesion can take part in disease progression.

- Cancer- Cancer cells can experience ER stress because of rapid growth, nutrient limitation and other unfavorable conditions. The UPR may support their survival under some conditions, while prolonged severe ER stress can also produce cell death.

## References

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