Cell Membrane Transport Mechanisms

• Diffusion refers to the magnitude and direction of the net movement of molecules or ions from an area of high concentration to an area of low concentration, crucial for homeostasis by ensuring uniform distribution of substances.
• Simple diffusion results from random movement and continues until a uniform distribution is achieved.

Flux

• Flux is the number of particles crossing per unit time and is concentration dependent.

Net Flux

• Net flux determines the gain or loss of molecules.
• It depends on factors such as temperature, molecule size, surface area, and the medium.
• Diffusion equilibrium is reached when the net flux is zero.
• Numerous collisions prevent long-distance travel in diffusion, significantly increasing diffusion time.
• Glucose takes a few seconds to diffuse 10 µm, while it takes 11 years to diffuse 10 cm. Diffusion time increases proportionately to the square of the distance
• Diffusion through membranes is typically 1,000 to 1,000,000 times slower.
• The magnitude of diffusion is described by the Fick diffusion equation (J = PA(Co - Ci)).
• "P" is the diffusion constant (MPC), representing the rate at which molecules pass through the membrane.
• "A" is the surface area
• "C" is the concentration gradient

Diffusion through membranes

• Nonpolar molecules have high permeability constants in the lipid bilayer.
• O2, CO2, and steroid hormones can dissolve in the hydrophobic region of the membrane.
• Ions diffuse through protein channels, which have a diameter only slightly larger than the ion.
• These channels are selective based on diameter and charge.

Role of Ion Movement

• Membrane potential separates charges across the plasma membrane.
• It provides an electrical force that influences ion movement.
• Like charges repel and opposites attract, leading to movement dependent on the electrochemical gradient, considering both concentration and charge.

Regulation of Ion Movement

• Ion channels can exist in either an open or closed state.
• Channel gating occurs, opening and closing channels and may occur many times per second.
• Three factors control gating:
• the binding of a molecule (ligand-gated)
• changes in charge (voltage-gated)
• physical deformation of membranes (mechanically gated).

Mediated Transport Systems

• Membrane proteins, known as transporters, transport more molecules that are large and/or polar via mediated transport.
• Characteristics include:
• typically being specific, binding to a specific site
• the process can occur in either direction, but is fewer than (1000x) than ion channels (bridge vs ferry).
• Speed depends on the saturation of the site, the number of transporters, and the speed and conformational changes of the transporters.
• Saturation is possible, unlike in simple diffusion.

Facilitated Diffusion

• The transport is still going downhill, requiring no energy.
• Glucose specific transporters (GLUTs) are used.
• Without GLUTS cells would be impermeable to glucose.
• A constant gradient exists, and different types have different genes and cell affinity.
• Insulin affects some types, recruiting them to the PM from vesicles.

Active Transport

• Moves a substance against a concentration gradient using pumps, exhibiting specificity and saturation and requires energy.
• Energy can be supplied by primary active transport or secondary active transport.

Primary Active Transport

• This involves a transporter that hydrolyzes ATP, an enzyme referred to as "ATPase".
• Covalent modulation alters the transporter's conformation.
• An example is Na+/K+-ATPase.
• Other types include Ca-ase and H+/H+-ase.

Secondary Active Transport

• This couples the movement of an ion down its gradient to transport another molecule. Uses the energy in the gradient instead of ATP.
• There are two binding sites: one for the ion (usually Na+) and one for the transported molecule.
• Maintenance of the gradient relies on primary active transport, with 10-40% of the cell's energy spent maintaining the Na+ gradient. -cotransport (symport) -counter-transport (antiport), both used in both cells.

Osmosis

• It is the net diffusion of H2O across the plasma membrane (PM) facilitated by aquaporins.
• These are membrane proteins that facilitate H2O movement with types and numbers differing in cells.
• This is especially important in kidney tubules.

Driving Force

• Pure H2O has a concentration of 55.5M
• Has a concentration of 54.5M in a 1M glucose solution.
• It depends on the number, not the nature, of the molecules.
• 1M glucose equals 1 Osm, regardless of size.
• Ionization doubles the concentration.
• 1 M glucose solution is equal to 0.5 M NaCl solution
• Osmolarity is the total solute concentration in a solution.
• Higher osmolarity leads to less H2O.
• Requires a semipermeable membrane (SPM).
• Volume changes only occur in the presence of a SPM.

Osmotic Pressure

• The amount of pressure necessary to prevent an inflow of H2O
• Increases with osmolarity
• Influences blood pressure (BP)

Osmosis - Cell Volume

• Non-penetrating solutes cannot cross the plasma membrane.
• Na+ and Cl- ions are typically outside.
• K+ and organic solutes are typically inside.
• Intracellular fluid typically has an osmolarity of 300 mOsm.
• Tonicity is determined by the concentration of non-penetrating solutes.
• Penetrating solutes do not contribute and have no impact on osmosis.
• Examples:
• a solution 300 mOsm glucose (non-penetrating) equals ~100 mOsm urea (penetrating) and is hyperosmotic
• a solution 100 mOsm NaCl (non-penetrating) equals ~100 mOsm urea (penetrating) and is isosmotic.

Endocytosis

• Pinocytosis involves "cell drinking" taking in ions, nutrients, and small molecules and occurs in all cells.
• Phagocytosis involves engulfing bacteria with pseudopods, forming phagosomes.

Endocytosis & Exocytosis

• Receptor-mediated endocytosis is receptor-dependent.
• It can be up or down regulated.
• This happens through clathrin-coated pits with examples including hormones, growth factors, and serum proteins
• Exocytosis replaces the plasma membrane and enables the release of plasma membrane-impermeable molecules, and peptide hormones.
• It is usually triggered by a calcium concentration increase.

Epithelial Transport

• There are two types: paracellular transport and transcellular transport.
• Involves water.
• Ions are actively transported, and H2O follows via osmosis.
• Roles include reabsorption from the kidneys and absorption from the intestines.

Nervous System Overview

• The divisions of the nervous system include the central (CNS) and peripheral (PNS) nervous systems.

Neurons

• Neurons are the units of the nervous system, with about 86 billion in the brain,.
• They release neurotransmitters, serve as integrators, and receive input from 100s or 1000s of other neurons with minimal mitosis.

Structure of Neurons (longest cells)

• The cell body contains the nucleus, ribosomes, and other organelles.
• Processes include dendrites, which are highly branched, and some cells have up to 400,000.
• Dendrites along with the cell body receive most of the information, that contain dendritic spines and ribosomes
• Axons carry information away from the cell body, ranging from a few microns to over a meter in length.
• Key structures include:
  • the initial segment (hillock)
  • trigger zone
  • collaterals
  • axon terminal
  • varicosities

Structure of Neurons

• Many axons are covered by myelin, consisting of 20-200 layers of modified plasma membrane.
• Myelin is formed by oligodendrocytes in the CNS, with each cell up to 40.
• Myelin forming cells include:
  • oligodendrocytes (CNS)
  • Schwann cells (PNS)
  • nodes of Ranvier (1-1.5 mm, regular intervals)
• Myelin speeds up signal conduction.

Axonal Transport

• Organelles and materials must be transported between the cell body and axon terminals.
• This can reach up to 1 meter in length.
• Components include:
• scaffolding of microtubules
• kinesins and dyneins.
• Types includeanterograde (kinesin), which is most common and carries cell body components to axon terminals like enzymes, nutrients, and vesicles.
• Retrograde (dynein) carries the cell body to terminals bringing recycled vesicles, growth factors, rabies, herpes, and tetanus.

Functional Classes of Neurons

• There are three classes:
  • afferent (toward CNS, sensory) (1)
  • efferent (away from CNS, motor) (10)
  • interneurons (within CNS) (200,000).
• Afferent neurons act as sensors located at their peripheral ends.
• They transmit signals to the brain or spinal cord, and are mostly located outside the CNS, with a central and peripheral process.
• Efferent neuron cell bodies and dendrites are typically inside the CNS, with nerves defined as bundles of afferent and efferent neurons.

Interneurons

• Interneurons are entirely located in the CNS and make up 99% of all neurons, these numbers vary.
• Some reflexes do not involve them.
• Millions are involved in complex processing.

Synapse

• A junction between two neurons that is highly specialized.
• Alters the chemical and electrical activity of another neuron by way of neurotransmitters.
• This can occur between a neuron and another neuron, or between a neuron and a muscle or gland.
• It occurs between an axon and a dendrite or cell body.
• There is pre- and post- synaptic neurons with one neuron normally receiving signals from thousands of others.

Glial Cells

• Make up 90% of neural cells, but neurons take up more space (90% of brain and spinal cord).
• Source of many CNS tumors.
• Types in the CNS include:
  • Oligodendrocytes form myelin covering
  • Astrocytes
  • Removes K+ and neurotransmitters
• Promotes blood/brain barrier
• Guides neurons during development
• Microglia are macrophage-like -Perform immune functions
• Ependymal cells line fluid cavities in the brain and spinal cord.
• Types in the PNS include:
  • Satellite Cells
  • Cover cell body
  • Regulate ECF are similar to astrocytes
  • Schwann Cells
  • Produce myelin sheath.

Neuronal Growth & Regulation

• Stem cells undergo differentiation.
• Processes that become axons/dendrites
• Growth cones assist in finding the correct route.
• Direction is determined by:
  • Glial cells
  • Cell adhesion molecules
  • Neurotrophic factors
• Family of proteins
• Typically released by the target cell & guide growing axons.
• Synapses form upon arrival and are sensitive during development.
• 50-70% of neurons undergo apoptosis
• Early plasticity leads to nearly ½ of an infant brain can be removed.
• Depends on no visual stimulation (1-2) and language (much older).
• Changes after maturity include:
• new synapses; associated with learning and minor production of new neurons

Neuronal Repair

• Damage to the outside CNS & cell body can be undamaged.
• Sequence of events:
  • The segment separated from the cell body degenerates and forms new growth cones (1 mm per day). -Crushing injuries lead to the loss of nearby oligodendrocytes and no effective regeneration occurs with severed axons

Neuronal Physiology

• Physiology is governed by laws of chemistry and physics pertaining to charge:
  • Like charges repel
  • Opposite charges attract
• Potential to do work
• electrical potential aka potential difference measured in units of 1 mV = .0001V.
• Resistance: that hinders electrical movement.
• Ohm's law: I= V/R (I = Current; V = Voltage; R = resistance)
• As resistance increases, current drops (lipids).

Resting membrane potential

• All cells have a charge difference across their membrane.
• The outside is the reference point while the inside is negative, -50-100mV.
• Generally -40 to -90 in neurons.
• Oppositely charged ions collect near the membrane with only a small fraction of total ions involved.

Equilibrium Potential

• Magnitude of RMP depends on:
  • the difference in ion concentration
  • membrane permeability.
• Equilibrium potential:
  • ion flows through until stopped by charge
  • charge difference @ that point is E.P.

Nernst Equation

• Describes E.P. for a particular ion given by the equation, where z is valance of the ion.

Goldman-Hodgkin-Katz (GHK) equation

• Vm= a modified version of the Nernst equation that takes into considered multiple ions in an open @ once state.
• Relative ion permeability: K= 1; Na = .04; Cl=.45.
• The RMP of neurons is -70mV, close to the E.P. for K+ (-90), and the is most permeable to K+.

Origin of Equilibrium Potential

• Electrogenic pump :
• establishes the gradient
• Diffusion of ions:
• depends on membrane permeability
• The balance of diffusion and pump mechanisms
• Some cells have ion channels that can be opened - neurons and muscle cells

Terms to describe changes in the value of the resting mebrane potential

• Depolarized: Cell becomes less negative than RMP
• Overshoot: inside of cell positive
• Repolarization: Return to RMP
• Hyperpolarization: more negative than RMP

Graded Potentials

• Changes in membrane potential confined to a small region of the plasma membrane (PM).
• Channels open letting ions flow.
• Many occur in a depolarizing or hyperpolarizing direction.
• Depending on the channel.
• Magnitude may vary, decremental.
• Summation is defined as the total effects of several events in sequence.

Action Potentials

Large changes in membrane potential (-70 to +30 mV).

• Occurs rapidly-few milliseconds and several hundred per second.
• Used for Long distance communication using Voltage Rated Channels
• Na+ = Faster, inactivation gate ("ball+chain")
• K+ = Slower

Action Potential Mechanism

• Initial depolarization that continues past a critical threshold creating positive feedback, that is halted. Then Voltage-gated Na+ inactivation gates & Voltage-gated K+ channels open triggering: Repolarization, brief after polarization while K+ channels slowly close.
• A threshold stimulus is typically 15 mV less than the RMP (-55mV).
• Subthreshold potentials don't reach the threshold (-56mV).
• A stronger stimuli doesn't mean stronger A.P.'s, and Magnitude is coded by #per unit time.
• Can be disrupted by Novocaine & Tetrodotoxin.

Refractory Periods

• Absolute refractory period:
  • voltage-gated Na+ channels are open or inactivated
  • inactivation gate.
• Relative Refractory period:
  • another A.P. is possible, but only with a stronger stimulus with hyperpolarization.
• Limits of A.P.
  • typical neurons is 100's per sec.
  • determines direction.

Action Potential Propagation

• Local depolarization causes changes in the adjacent membrane.
• Can only move forward due to the Refractory period.
• Speed is increased with larger diameter and myelin.
• Myelin prevents the movement of ions. A.P. propagation only occurs @nodes of Ranvier via saltatory (to leap) conduction, FASTER
• A.P. appears to jump:
  • 0.5 m/s (1mi/hr) in small, non-mylinated (4sec)
  • 100m/s (225 mi/hr) in large diameter myelinated (.02sec)

Action Potential Initiation

• Receptor potential: a type of graded potential used by sensory neurons
• Synaptic potential: Graded potential generated by synaptic input
• Pacemaker potential: a spontaneous change in neuron's membrane potential via continuous changes in membrane potential.

Functional Anatomy & Synapses

• There are 100 trillion synapses in CNS that can be:
  • excitatory; Closer to threshold
  • inhibitory; Stabilized
• Convergence & divergence
• Many thousands may converge on one cell or one cell may effect many more.

2 Types of Synapses

• Electrical: Gap functions can be Cardiac Muscle
• Now known to be relatively widespread in the nervous system
• Chemical Synapses includes:
  • axon terminals, synaptic vehicles, postsynaptic density, and the synaptic cleft(10-20nm) that contains neurotransmitter and cotransmitter.

Mechanism & Neurotransmitter Release

• Prior to A.P. arrival vesicles are docked within active Zones using: SNARE Proteins is Soluble N-ethylmaleimide used to Sensitive fusion attachment prptien recepties. Ca2+ channels that are triggered by a A.P, opens causing ions such as Ca2+ to flow in.
• Ca2+ Leads to vesicle fusion that: Binds to synaptotogmins which leads to Snare Complex Canformation change.
• Causes 2 Vesicle Fates: fusion and kiss and run fusion

Activation of Post Synaptic Cell

• A fraction of neurotransmitters bind to receptors with differing Beceptor types such as

• Ionotropic Receptas that contains ion channels that are active and cause a short delay.
• Metabotrophic Receptor and causes a second messenger that is active.
• All synapses are:transient and are actively transported back into a presynaptic membrane and diffuse away All can be transformed into inactive substances
• 2 types of chemical Synapses: excitatory/inhibitory.

Excitatory

• Cause Depolarization by opening nonselective Na+ & K+ channels that creaties epsp (excitatory post sypaptic potential) that are Graded potentials

Inhibitory Synapse

• Cause Hyperpolarizing with IPSP (inhibitory post synaptic potential) that just Stabilize the membrane at its BMP.
• Lowers the chance of an A.P. happening through Mecanisms such as:
• opening of K+ channels closer to its E.P, or of -Cl channels, which would stabilize R.M.P.
• if Cell actively regulates Cl may lead to hyper polarization

Synaptic Integration

• A single EPSP typically is not enough (5 mV vs. X mV threshold).
• MP is the product of the synapses active @ a moment with perhaps 1000's of stimuli active @ any given time:
  • temporal summation
  • spatial summation
• neutraliation
• Synapse impacts are certain area of the P.S and are less intense at initial segments but cause: higher density of Nat channels and creates in Location of a synapse an: greater initial change & less change if further down a branch or dendrite.

Potentials

• Cause longer loating potentials, and multipule APs may form that occur in bursts.

Synaptic Strength

• Postsynaptic potentiation allows for variability dependent on Ca 2+ release build up from signals from:
• Axo-axonic synapse that is: Pre/postsynaptic inhibition or facilitation Mechanism= Alter neurotransmitter synthesis caused by 2+ levels and from effects of Auto receptors.

Synactic Strength - Postsynaptic Mechanisms

• Dependent on the type of receptors present that cause greater influence.

of presnt receptors causes up and down Regulation & receptor #'s which triggers: Receptor desensitization.

• Synapses - Is commonly affected with Drugs/ diseases

Common mechanisms caused by neurological active drugs

• The influence synthesis, storage, release, and, receptor activation of neotransmitter.
• Example Drugs
• tetanw damages SNARE Proteins and affects inhibitor nearons.
• Botulism also destroySNARE Proteins, that targets synapses that activate excitatory dekatak musceels.

Calciseptine - Ca+ blocker

Is a neurotoxin that blocks 2+ channels and the release of NT and is the 1st discovered specific Ca 2+ blocker.

Neurotransmitters & Neuromodulators

• Neuro modulators are
• alterd the effectiveness @ the synapse.
• change the rate of post synaptic cells and Synpatoc transmissions
• Are distinct from neurotransmitters and influence ion channels and the rate of EPSP and IPSP transmission.
• Transmisions by neurotransmiiters can vary from seconds to minutes.

Acetylcholinesterase Transmission

• Major neurotransmission is in the PNS & in the brain.
• Cholinergic neurons (Release Ach): Are Located on pre- & post synaptic membranes is taken up into pre syn. membrane and disrupted bySarin.
• Comes in 2 different types:
• Nicotinic receptors are ion channels that are important in attention, learning, reward pathways
• Muscarinic: Alters that are activities Enzymes transmission and the use of ion channels, but can be blocked with Atropine