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1.3 Transport mechanisms

byMedHawk • • 2 min read
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1.3 Transport mechanisms



    The plasma membrane, often referred to as the cell membrane is made of phospholipid bilayer. Phospholipid is made of hydrophilic head and hydrophobic tail. Phospholipids form a bilayer in a manner that inner portion is hydrophobic and outer portion is hydrophilic. This structure allows some substances to move though while not allowing others from passing through. This semipermeable barrier separates the cell's internal environment from the external world and acts as a gatekeeper, controlling the movement of substances in and out of the cell. Understanding how molecules move across this barrier is essential for comprehending cellular processes, drug delivery mechanisms, and various physiological functions. 

    The phospholipid bilayer consists of two layers of phospholipid molecules arranged in a specific orientation.
  1. Hydrophilic heads: The outer portions of both layers are composed of hydrophilic (water-loving) phosphate heads, which face the aqueous environments on both sides of the membrane. 
  2. Hydrophobic tails: The inner portion of the bilayer contains hydrophobic (water-fearing) fatty acid tails, which face each other and create a water-resistant core.

1. Passive Transport

    Passive transport is a mechanism by which molecules move across the plasma membrane without the expenditure of ATP. This process occurs along the concentration gradient, from an area of higher concentration to an area of lower concentration. Simple diffusion and facilitated diffusion are two types of passive transport.

1) Simple diffusion

    Simple diffusion is the most basic form of passive transport. In this process, molecules move randomly from an area of high concentration to an area of low concentration until equilibrium is reached.

Key characteristics of simple diffusion:
  • No energy expenditure
  • Follows the concentration gradient
  • Depends on the permeability of the membrane
  • Affected by factors such as temperature and molecule size
Examples of molecules that is transported via simple diffusion:
  • Oxygen
  • Carbon dioxide
  • Ethanol

2) Facilitated diffusion

    Facilitated diffusion is a form of passive transport that involves the assistance of membrane proteins. These proteins act as channels or carriers, allowing specific molecules to pass through the membrane more easily.

Types of facilitated diffusion:

1. Channel-mediated diffusion:  Channel proteins allow molecules to pass through them. These channels can be:
  • Always open (e.g. aquaporins for water transport)
  • Gated (e.g. ion channels that open or close in response to stimuli)
2. Carrier-mediated diffusion: Carrier proteins bind to specific molecules and undergo conformational changes to transport them across the membrane.

Examples of molecules transported via facilitated diffusion:
  • Glucose (via GLUT transporters)
  • Ions (through ion channels)
  • Amino acids

3) Osmosis

    Osmosis is a special case of passive transport involving the movement of water molecules across a semipermeable membrane. Water moves from an area of higher water concentration (lower solute concentration) to an area of lower water concentration (higher solute concentration). Aquaporins are specialized water channels that facilitate the rapid movement of water molecules across the membrane. Water can pass through the plasma membrane with or without channel proteins. However, without aquaporins, only limited amount of water can be moved through the membrane.

Importance of osmosis:
  • Maintains cell volume
  • Maintains water balance in organisms
  • Relevance in medical treatments (e.g. IV fluids)

2. Active Transport

    Active transport is a mechanism by which cells move molecules across the plasma membrane against their concentration gradient. This process requires energy, typically in the form of ATP (Adenosine Triphosphate).

1) Primary active transport

    Primary active transport involves the direct use of ATP to move molecules across the membrane. The most well-known example of this is the sodium-potassium pump (Na+/K+-ATPase).

Sodium-Potassium Pump:
  • Moves 3 Na+ ions out of the cell and 2 K+ ions into the cell per ATP molecule hydrolyzed
  • Maintains the electrochemical gradient across the membrane
  • Essential for nerve impulse transmission and many other cellular processes
Other examples of primary active transport:
  • H+/K+ ATPase in stomach cells (for acid secretion)
  • Ca2+ ATPase in muscle cells

2) Secondary active transport 

    Secondary active transport, also known as coupled transport, uses the electrochemical gradient established by primary active transport to move molecules against their concentration gradient.

Types of secondary active transport:
  1.  Symport: The carrier protein moves two different molecules in the same direction. (Sodium-glucose co-transporter (SGLT) in intestinal cells)
  2. Antiport: The carrier protein moves two different molecules in opposite directions. (Sodium-calcium exchanger in cardiac muscle cells)
Importance of secondary active transport:
  • Nutrient absorption in the intestines
  • Neurotransmitter reuptake in synapses
  • Ion balance in various tissues

3. Endocytosis and Exocytosis

    Endocytosis and exocytosis are processes involved in the movement of large molecules or particles across the membrane using vesicles.

1) Endocytosis

Endocytosis is the uptake of material into the cell
  • Phagocytosis: "Cell eating" - engulfing large particles
  • Pinocytosis: "Cell drinking" - taking in fluids and dissolved substances
  • Receptor-mediated endocytosis: Specific uptake of molecules bound to receptors

2) Exocytosis

The release of material from the cell
  • Secretion of hormones, neurotransmitters, and other substances

4. Interplay of Different Transport Mechanisms

    While we've discussed different transport mechanisms separately, it's important to understand that these mechanisms often work together in complex ways to maintain cellular homeostasis.

1) Glucose Transport

    Glucose, a primary energy source for cells, is transported through both facilitated diffusion and secondary active transport. This dual system allows for efficient glucose uptake under various conditions and in different cell types.
  1. GLUT transporters: These facilitate the passive diffusion of glucose along its concentration gradient. Different GLUT isoforms are expressed in various tissues, allowing for tissue-specific regulation of glucose uptake.
  2. SGLT transporters: These use secondary active transport to move glucose against its concentration gradient, coupled with sodium transport.

2) Ion Transport

    Ions, being charged particles, cannot easily pass through the hydrophobic core of the plasma membrane. Their transport is primarily mediated by:
  1. Ion channels: These allow for facilitated diffusion of specific ions down their electrochemical gradient.
  2. Ion pumps: These use ATP to actively transport ions against their concentration gradient, such as the sodium-potassium pump.

3) Lipid Transport

    While small, nonpolar molecules can diffuse directly through the lipid bilayer, larger lipid molecules often require specialized transport mechanisms.
  1. Flip-flops: Process of moving phospholipids between the inner and outer leaflets of the membrane.
  2. Lipid transfer proteins: These facilitate the movement of lipids between cellular compartments.

4) Aquaporins

    Aquaporins are specialized water channels that facilitate the rapid movement of water molecules across the membrane. They are crucial for:

  • Maintaining water balance
  • Urine concentration in the kidneys
  • Secretion of various bodily fluids


5. Transport in Specialized Cells and Tissues

    Different cell types have adapted their transport mechanisms to suit their specific functions.

1) Epithelial cells

    Epithelial cells line various organs and cavities in the body. They often exhibit polarized transport, with different transport proteins on their apical and basolateral surfaces.
  • Apical surface: Sodium-glucose cotransporters for nutrient absorption
  • Basolateral surface: Glucose transporters for releasing absorbed glucose into the bloodstream

2) Neurons

    Neurons rely heavily on ion transport for their function:
  • Sodium and potassium channels for action potential generation and propagation
  • Sodium-potassium pump for maintaining the resting potential and enabling action potential
  • Calcium channels for neurotransmitter release
  • Neurotransmitter transporters for reuptake at synapses

3) Kidney Cells

    Kidney cells use a combination of passive and active transport mechanisms to filter blood and maintain electrolyte balance:
  • Aquaporins for water reabsorption
  • Various ion channels and transporters for electrolyte balance
  • Glucose transporters for reabsorption of filtered glucose

6. Regulations of Transport Mechanism

    The transport of substances across the plasma membrane is tightly regulated to maintain cellular homeostasis and ensure appropriate responses to environmental changes. This regulation occurs at multiple levels.

1) Expression of Transport Proteins: 

    Cells can adjust the number of transport proteins present in the plasma membrane through several mechanisms.

  • Transcriptional regulation: Cells can increase or decrease the transcription of genes encoding specific transporters. For example, in response to hypoxia, cells upregulate the expression of glucose transporter 1 (GLUT1) to enhance glucose uptake and anaerobic metabolism
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  • Post-transcriptional regulation: This includes processes like mRNA stability and alternative splicing. Some transporters have splice variants with different functional properties or subcellular localizations. 
  • Protein trafficking: Cells can regulate the insertion or removal of transporters from the plasma membrane. A classic example is the insulin-stimulated translocation of GLUT4 glucose transporters from intracellular vesicles to the plasma membrane in muscle and fat cells.

2) Post-translational Modifications

    Various post-translational modifications can alter the activity or localization of transport proteins. 

  • Phosphorylation: Many transporters are regulated by phosphorylation. For instance, the sodium-potassium-chloride cotransporter (NKCC) is activated by phosphorylation in response to cell shrinkage. 
  • Ubiquitination: This modification often targets proteins for degradation. The epithelial sodium channel (ENaC) is regulated by ubiquitination, which controls its surface expression and activity.  
  • Glycosylation: This can affect protein stability and trafficking. The glucose transporter GLUT4 requires proper glycosylation for its insulin-responsive trafficking.

3) Hormonal Regulation

    Hormones play a crucial role in regulating transport processes across various tissues:

  • Insulin: Besides its effect on GLUT4 translocation, insulin also stimulates the sodium-potassium pump (Na+/K+-ATPase) activity in many tissues, enhancing cellular potassium uptake. 
  • Aldosterone: This hormone increases the expression and activity of ENaC in the kidney, promoting sodium reabsorption and potassium excretion. 
  • Antidiuretic hormone (ADH): ADH increases water permeability in the kidney collecting duct by stimulating the insertion of aquaporin-2 (AQP2) water channels into the apical membrane.

4) Feedback Mechanisms

    Transport processes are often subject to feedback regulation based on the concentrations of transported substances.

  • Allosteric regulation: Many transporters have binding sites for regulatory molecules that can enhance or inhibit their activity. For example, the mitochondrial ATP/ADP translocase is inhibited by high ATP levels. 
  • Substrate-induced regulation: Some transporters are regulated by their own substrates. The dopamine transporter (DAT) undergoes rapid internalization upon binding to its substrate, dopamine.

5) Membrane Environment

    The lipid composition and organization of the plasma membrane can significantly affect transporter function.

  • Lipid rafts: These specialized membrane microdomains can concentrate or exclude specific transporters, affecting their activity. For instance, the serotonin transporter (SERT) is regulated by its association with lipid rafts
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  • Membrane fluidity: Changes in membrane fluidity can affect the activity of many transporters. This is particularly relevant in conditions like hypothermia or in diseases affecting membrane composition.


7. Clinical Relevance

    Many diseases involve alterations in cellular transport, and numerous therapeutic interventions target these processes. 

1) Channelopathies

    These are diseases caused by mutations in ion channel genes. 

  • Long QT syndrome: Mutations in potassium channel genes can lead to prolonged cardiac action potentials, increasing the risk of life-threatening arrhythmias. 
  • Myotonia congenita: Caused by mutations in the chloride channel gene CLCN1, leading to muscle stiffness and delayed relaxation after contraction.

2) Transporter-related Diseases

  • Gitelman syndrome: A disorder of the thiazide-sensitive sodium-chloride cotransporter (NCC) in the kidney, leading to hypokalemia and metabolic alkalosis.
  • Glucose-galactose malabsorption: Caused by mutations in the sodium-glucose cotransporter 1 (SGLT1), resulting in severe diarrhea and dehydration in infants.

3) Drug Targets and Delivery

    Many drugs target specific transporters or channels.

  • Proton pump inhibitors: These drugs inhibit the H+/K+-ATPase in gastric parietal cells, reducing acid secretion and treating conditions like gastroesophageal reflux disease (GERD). 
  • Selective serotonin reuptake inhibitors (SSRIs): These antidepressants target the serotonin transporter (SERT), increasing serotonin levels in the synaptic cleft. 
  • SGLT2 inhibitors: A new class of diabetes medications that inhibit glucose reabsorption in the kidney by targeting the sodium-glucose cotransporter 2. 
  • Antifungal Agents: Many antifungal drugs target fungal plasma membrane proteins. For instance, they may inhibit enzymes like H+-ATPase, which is crucial for maintaining ion gradients across the membrane in fungi like Candida glabrata
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  • Bicuculline (BIC): This is a GABA_A receptor antagonist that affects neuronal activity by altering the lipid organization of neuronal plasma membranes. It is used in research to study synaptic plasticity and neuronal processes
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  • HIV-1 Gag Protein Inhibitors: These target the assembly of HIV-1 virions at the plasma membrane. The matrix domain of Gag proteins interacts with phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)], which is crucial for viral assembly and membrane binding
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4) Cancer Therapy

  • Multidrug resistance: Cancer cells often overexpress efflux transporters like P-glycoprotein, which can pump out chemotherapeutic drugs. Inhibitors of these transporters are being developed to enhance chemotherapy efficacy.
  • Targeted drug delivery: Nanoparticles and antibody-drug conjugates are being designed to exploit specific transport mechanisms to deliver drugs selectively to cancer cells.

5) Poisons targeting the plasma membrane

  • Tetrodotoxin (TTX): This is a potent neurotoxin that targets voltage-gated sodium channels in neuronal plasma membranes, blocking nerve signal transmission. It is often used in research to silence neuronal activity by preventing action potential generation
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  • Dengue Virus (DENV): Although not a traditional poison, DENV infection affects plasma membrane physiology by inducing reactive oxygen species (ROS) production, which can alter membrane potential and permeability, impacting cellular function and integrity
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Conclusion

    Today we discussed about transport mechanisms across the cell membrane. The selective permeability of the plasma membrane made of phospholipid bilayer is fundamental to cellular function and overall physiology. Various transport mechanisms work together to ensure that cells maintain their internal environment while interacting with the external world. These transport mechanisms are tightly regulated by our body via multiple processes. Due to their significance for our body, there are lots of therapies and drugs targeting the transport mechanisms. 





























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