Cell Membrane: Composition, Permeability, Function

• Cells have cell membranes, which would cause significant changes if removed.
• Cell membranes can be compared to non-biological things.

Selective Permeability and Purpose

• Selective permeability of the cell membrane serves different purposes
• Glucose, fatty acids, amino acids, and oxygen are selectively permeable for energy requirements
• Hormones, neurotransmitters, cytokines, and ions are selectively permeable in order to receive or send signals or messages
• Carbon dioxide, water, lysosomal/proteasomal breakdown products are selectively permeable for waste removal
• Ions selectively permeable for membrane potential
• Water selectively permeable for osmosis/water balance

Cell Membrane Composition and Function

• The human body comprises over a hundred trillion individual cells
• Cells can be considered small factories working continuously
• Cells can be thought of as microscopic human beings, with a miniature brain (DNA) and an energy source (mitochondria energy-producing)
• Cells can communicate with one another as well as produce proteins and hormones
• The cell membrane has a thickness of 7.5-10 nanometers
• A nanometer is 1x10-9 m, or one billionth of a meter
• The cell membrane's most important organelle surrounds all living cells
• The membranes that surround the nucleus and other organelles are nearly identical to the cell membrane
• Phospholipids create a thin, flexible sheet
• Proteins "float" in the phospholipid sheet like icebergs
• Carbohydrates protrude from the proteins

Cell Membrane Components

• Cell membranes consist of Cholesterol, Phospholipids, Sphingolipids, Carbohydrates, and Proteins
• Phospholipids and Sphingolipids form a lipid bilayer
• This bilayer functions as a selective barrier between the cytosol and external environment
• Carbohydrates form Glycolipids and Glycoproteins
• Glycolipids and Glycoproteins provide structural stability, cell recognition, and immune response
• The plasma and organelle membranes contain 40-80% lipid
• Hydrophobic lipids, also known as "fatty acid tails", are water insoluble/fat soluble and are on the inside of the membrane
• Hydrophilic lipids, also known as "heads", are polar/water soluble/fat insoluble and are on the outside of the membrane
• Phospholipids are the most abundant lipid in all membranes
• Cholesterol influences the fluidity of the membrane
• Cell membranes are "selectively permeable"

Membrane Proteins

• Membrane proteins float in a "sea" of membrane lipids
• The number of proteins varies depending on the function of the membrane
• Protein:lipid ratio varies from 1:4 to 4:1 depending on the membrane
• Protein components are asymmetrically situated in the membrane
• Membrane proteins are classified by structure or function
• Integral (transmembrane) proteins span the membrane.
• Peripheral proteins are located on the membrane's surface
• Lipid-anchored proteins are attached to the lipid layer
• Membrane proteins can be categorized according to their structure or function
• Based on structure, there are lipid-anchored proteins, integral proteins, and peripheral proteins
• Membrane proteins can function as membrane transporters, structural proteins, membrane enzymes, and membrane receptors
• Membrane proteins can form cell junctions, and the cytoskeleton
• Membrane proteins can be open channels or gated channels
• Gated channels include mechanically gated, voltage-gated, and chemically gated channels

Membrane Protein Functions and Classes

• Membrane transporters transport molecules across the membrane
• Structural proteins anchor the cytoskeleton
• The plasma membrane possesses membrane receptors
• Membrane receptor action includes a ligand binding to a cell membrane receptor protein
• And a ligand-receptor complex triggers intracellular response
• There are four Membrane Receptor Categories
• Receptor-channel
• Receptor-enzyme
• G protein-coupled receptor
• Integrin receptor

Glycocalyx

• Glycocalyx, the outer layer on the cell membrane, consists of glycoproteins
• Its carbohydrate side chains serve as binding sites for extracellular matrix components such as fibronectin
• Glycocalyx coating on the outside of the cell membrane has a negative charge playing a role in cell-to-cell contact and adhesions
• The glycocalyx is an outer layer and a structural part of the cell membrane connecting to the extracellular environment

Membrane Dynamics and Transport

• Membrane dynamics depend on membrane properties, transported molecule properties, and energy availability
• Membrane properties and structures: solubility, membrane proteins, channels, receptors, carrier proteins etc.
• Properties of transported molecules and substances: size, electrical charge, solubility, presence of a gradient
• ATP or kinetic energy is needed if energy is required for transport
• Energy requirements can be met passively or actively
• Requiring no energy other than that of molecular motion of diffusion
• Or requiring energy from ATP
• Physical requirements for movement
• Molecule goes through the lipid bilayer
• Mediated transport requires a membrane protein
• Uses a membrane-bound vesicle for transport
• There are two forms of diffusion: simple diffusion and facilitated diffusion

Diffusion

• The key concepts of diffusion: concentration gradient driven and no ATP energy required (passive)
• Energy to diffuse is obtained from kinetic energy of the molecules
• Solubility properties of the molecule determine the form of diffusion
• Fat soluble molecules that are non-polar dissolve in cell membrane in simple diffusion
• Water soluble molecules require membrane proteins for facilitated diffusion
• Gases are fatsoluble and can dissolve in cell membranes
• Ions are water-soluble molecules and require proteins

Fick's Law

• Fick's Law of Simple Diffusion depends on: surface area, concentration gradient, membrane permeability, membrane thickness
• Movement of gases is facilitated by being lipophilic and dissolving in cell membranes

Facilitated Diffusion

• Facilitated diffusion requires no ATP energy and is concentration gradient driven
• Facilitated diffusion needs the help of membrane proteins as they cannot dissolve in the cell membrane

Membrane Proteins in Facilitated Diffusion

• Carrier proteins bind molecules and change shape to transport them
• Channel proteins, such as open or leaking channels, create a water-filled pore
• Glucose uptake via GLUT is an example of facilitated diffusion
• Gated ion channels only open under certain conditions, similar to a tollbooth gate, and can be either electrical or chemical events
• Voltage-gated channels open due to electrical events such as the firing of an action potential
• Ligand-gated channels, in contrast, open due to chemical signals such as a hormone binding to the channel

Primary Active Transport

• In primary active transport, chemical energy is supplied by the hydrolysis of ATP
• An example is the Na+/K+ pump, which is an enzyme (Na+/K+-ATPase) and a carrier protein
• Hydrolysis of 1 ATP molecule pumps 3 Na+ ions outside the cell and 2 K+ ions back into the cell against their concentration gradient
• The high energy phosphate group can then react with a protein via Phosphorylation modifying the functions of that protein

Na+/K+ Pump Mechanism and Co-transport

• The Na+ / K+-ATPase pump = carrier protein that actively pumps Na+ out of the cell and K+ into the cell, against their concentration gradients
• It is a primary active membrane transporter
• Co-transport relies on the transport from one substance providing the energy to power another substance that also moves providing energy
• For example: Na+-Glucose Co-Transporter in epithelial cells of the small intestine or proximal renal tubules
• Glucose has to enter the epithelial cells AGAINST its concentration gradient
• This is achieved by membrane carrier protein called the Na-Glucose Co-Transporter

Glucose Transport

• Glucose transporters transfer glucose to ECF by facilitated diffusion
• Na+-K+-ATPase pumps Na+ outside of the cell, maintaining a low ICF Na+ concentration
• Potential energy from Na+ concentration gradient helps move glucose against its concentration gradient

Endocytosis and Exocytosis

• Endocytosis (1-4) transports vesicle with receptors moves to the cell membrane
• Exocytosis (7-9) transports vesicle and cell membrane that fuse for membrane recycling
• Ligand binds to a membrane receptor and migrates to a clathrin-coated pit which is then endocytosed, and looses clathrin coat
• Receptors and ligands then separate and ligands goes to lysosomes or Golgi for processing
• And Receptors and ligands separate into an endosome

Receptors and Ligands

• Water-soluble (protein) ligands ALWAYS bind to cell membrane receptors
• Fat-soluble ligands CAN bind to cell membrane receptors, but can ALSO bind to intracellular receptors (cytoplasmic or nuclear)
• Ligand-receptor interaction acts like a lock-and-key
• Ligand can be hormone, neurotransmitter or cytokine
• Receptor may be on membrane, or in cytoplasm or nucleus
• The cellular effect is that binding of ligand activates a mechanism leading to an effect

GPCRs: G-Protein Coupled Receptors

• Ligand binding to a G protein-coupled receptor opens an ion channel or alters enzyme activity
• The Ligand -Receptor complex activates a membrane protein called G-PROTEIN (“SIGNAL TRANSDUCER”)
• It leads to two possible intracellular mechanisms:
• Activation of an Amplifying Enzyme (AE)- second messenger system
• Activation of a nearby ion channel to open, allowing the flow of ions through the channel
• Ligand does NOT enter the cell but merely leads to the switching on of a mechanism
• G-proteins are “Signal Transducers
• There are also Amplifying Enzymes (AE) and Second Messengers

Receptor Enzyme Process

• In the Receptor-enzyme process, The receptor is connected with an enzyme on the inside of the cell membrane
• Forming a "RECEPTOR-ENZYME" the enzyme leads to the activation of intracellular proteins
• Via PHOSPHORYLATION (addition of a phosphate group)
• For example, insulin-receptor is a receptor-tyrosine kinase receptor found in muscle cells.
• Another class is Ligand-gated ion channel receptors
• In this case, this channel acts as a receptor
• For example Nicotinic Acetylcholine Receptor (nAChR) is a receptor with two bonding sites
• That are a gated ion channel
• Activating depolarization

Fat-soluble ligands

• Fat-soluble ligands bind to intracellular receptors
• The receptors will then act in the nucleus
• Leading to the synthesis of new proteins
• Blocking the synthesis of proteins

Electrical Properties of Cell Membranes

• Excitable cells: Nerve cells; skeletal muscle cells and heart muscle cells.
• An electrical potential difference (Volt) exists between the inside and outside of the cell membrane.
• Because of the chemical electrical disequilibrium of electrically charged atoms.
• Specifically Na+; K+; Ca2+; Cl-; etc.
• When the cell is at rest, the potential difference is at a certain level
• That is labeled the Resting Membrane Potential.
• And in the Resting Membrane Potential the membrane is undisturbed as the ion channels are closed.
• Now take that cell membrane is disturbed by and impulse or whatever else.
• Well the ion channels do not like that.
• And because the ion channel is disturbed they open or they close depending on the ion.
• And because they open/close, a dramatic cross-membrane movement of ions occurs as they try to "reach" chemical and electrical equilibrium.
• "Examples" Na+ streams into the cell - depolarizes membrane.

Membrane Potentials and Neuron Action

• As you now know, The opening and closing of various ion channels occurs in a specific set of events.
• This brings about an electrical event called the Action Potential.
• A large sum of Action Potentials is achieved by many of the aforementioned events occurring.
• Which causes an electrical impulse (wave) to be formed that is in turn then conducted along the cell membrane. From 1 cell to the next.
• Lastly, but possibly most important: In nerve cells, those electrical impulses are messengers. Releasing a neurotransmitter at the synapse.
• A resting membrane separates two areas with different electrical charges
• A potential difference develops across the membrane
• Charged particles/ions are prevented from flowing by closed gated ion channels
• The inside of the cell is more negative relative to the outside
• With open channels, ions flow depending on their electrical gradients, changing the membrane potential
• Comparing the cell membrane to the poles of a battery. It is the charge difference that is key

Action Potential Phases

• A voltmeter measures the difference in electrical charge inside and outside of a cell
• The recorded value is called membrane potential difference
• Resting neurons have closed ion channels
• The electrical charge on the inside of the cell membrane is 70 mV lower than the outside
• Since the outside is set to zero, the resting membrane potential difference is -70 mV
• When a membrance depolarizes the inside charge becomes more positive due to inflow of + charged Na+ ions
• Repolarization means that the charge on the inside becomes more negative
• Resting potential is at the closure of Na+ Channels, while K+ Channels are open allowing + charged K+ ions to flow out.

Neuron action

• Na stops streaming in, and you get K+ streaming out of cell.
• The result is repolarization which returns cell to a resting membrane potential of -70
• Na+ channels will open and Na+ streams into the cell bringing about Depolatization
• Now that that is done, the Na+ channels need to close, which happens, and K+ channels need to open as well.
• Sometimes the K+ channels remain open and K+ is ejected all the way out of the cell.
• This can cause the area that just occurred to be more negative.
• This would be classified as HYPERPOLARIZED.

Restoring Ion Imbalance

• Due to all of the polarization and action potentials, ions can get unbalanced
• You need to do something such as the Na+ / K+ Pump or it ends poorly
• Ions get depleted, increase, and the gradients are gone
• The goal in such a situation is getting the gradients, and ions back to where they need to be.

Recapitulation

• Excitable Cells : nerve cells, Skeletal Muscle cells and heart Muscle Cells. An electrical potential difference (Volt) exists between the inside and outside the cell membrane due to chemical and electrical disequilibrium of electrically charged atoms (ions: Na+; K+; Ca2+; Cl-; etc.
• The cell membrane cannot just be disturbed whenever. All the ions are shut and the cell membrane cannot accept any type of energy coming it’s way.
• "Electrical Impulses Lead to messengers, and eventually release a neurotransmitter.