Basic functions of cells

Basic functions of cells
Instructor: Li Li Department of Physiology Jining medical college Office: 0850 physiological sciences

Basic functions of cells
⑴ Structure of cell membrane and membrane transport. ⑵ Signal transduction of cell membrane. ⑶ Membrane potentials and action potentials.

⑴ Structure of Cell Membrane and Membrane Transport
Membranous structure. Transport of substance through the cell membrane. ① Simple diffusion. ② Protein-Mediated transport. Facilitated diffusion and active transport. ③ Endocytosis and exocytosis.

Figure Cells.

Figure Cell membrane.

Membranous Structure Functions ① Physical barrier.
② Regulation of exchange with the environment. ③ Communication between the cell and its environment. ④ Structural support.

Figure Fluid mosaic model.

Membranous Structure Structure ( fluid mosaic model)
① Composed of mainly lipids and proteins. ② Lipid bilayer with proteins embedded in a lipid matrix. ③ Carbohydrate groups attached to proteins and lipids. ④ Cholesterol is inserted into the lipid bilayer.

Figure The lipid bilayer.
hydrophilic hydrophobic Figure The lipid bilayer.

Lipid bilayer hydrophilic amphipathic. hydrophobic phospholipid
Fatty acid chains Fatty acid chains hydrophobic hydrophobic Charged region

Figure Cholesterol in the membrane.

Figure Proteins in the membrane.

Proteins Integral proteins Peripheral proteins Amphipathic
Proteins can function as carrier, channel, ion pump( integral proteins) and enzyme and some controllers of intracellular function( peripheral proteins). Proteins Integral proteins Peripheral proteins Amphipathic Not amphipathic

Figure Carbohydrates in the membrane.
Identify and interact Figure Carbohydrates in the membrane.

Flash Fluid mosaic model.

Transport of Substance Through the Cell Membrane
Simple Diffusion Protein-Mediated Transport ① Facilitated diffusion via carrier. ② Facilitated diffusion via ion channel. ③ Primary active transport. ④ Secondary active transport. Endocytosis and Exocytosis

Figure Process of simple diffusion.
Random thermal motion Simple diffusion Figure Process of simple diffusion.

Simple Diffusion The movement of molecules from one region to another solely as a result of their random thermal motion is known as simple diffusion. ① Molecules move from an area of higher concentration to lower concentration, and simple diffusion is not coupled with energy( passive transport). ② The magnitude of the net flux depends on: concentration difference; temperature; mass of the molecule; surface area; lipid solubility of the molecule. ③ Small non-polar substances (oxygen, carbon dioxide, fatty acids, and steroid hormones) can diffuse easily through the membrane.

Figure Different permeability across the membrane.
Inside Outside Nonpolar molecules Polar molecules Figure Different permeability across the membrane. The major factor limiting diffusion across a membrane is the hydrophobic interior of its lipid bilayer.

Figure The net flux by simple diffusion.
Temperature

Flash Process of protein-mediated transport.

Protein-mediated transport The transport of slight polar molecules or charged ions is mediated by proteins within the membrane. Facility diffusion ① Not energy (ATP) dependent. ② Move molecules from a higher to a lower concentration ( passive transport). ③ Movement of molecules depends on the concentration gradient( energy source). ④ Facilitated diffusion via carrier( transporter is carrier) and facilitated diffusion via channel( transporter is channel).

Protein-mediated transport Facilitated diffusion via carrier Characteristics: ① Glucose and amino acid can be transported via carrier. ② Specificity. ③ Competition. ④ Saturation.

Figure Facilitated diffusion via carrier.

Flash Facilitated diffusion via carrier.

Figure The saturation of facilitated diffusion via carrier.

Protein-mediated transport Facilitated diffusion via channel Characteristics: ① Charged ions such as sodium, potassium, chloride ,calcium can be transported via channel. ② The direction and magnitude of ion flux depend on both the concentration difference and electrical difference ( electrochemical gradient). ③ Selectivity determined by size of pore and/or charges lining the inside of channel . ④ Ion channel can exist in an open or closed state, and the process of opening and closing ion channel is known as channel gating. ⑤ There is three type of channel: voltage-gated; chemically-gated, mechanically-gated.

Flash Facilitated diffusion via channel.

electrochemical gradient:
The direction and magnitude of ion flux depend on both the concentration difference and electrical difference.

Figure Selectivity of the ion channel.
Selectivity determined by size of pore and/or charges lining the inside of channel .

Protein-mediated transport Active transport Active transport uses energy to move a substance uphill across a membrane( against the substance’s electrochemical gradient), and they are often referred to as “pumps”. ① Primary active transport: energy is derived from breakdown of ATP. ② Secondary active transport: energy is derived from ion concentration difference across a membrane, which is already created by primary active transport.

Protein-mediated transport Primary active transport Sodium-potassium pump Function: ① Three sodium ions out of cell and two potassium ions in. ② Maintain the characteristic distribution of high intracellular potassium and low intracellular sodium. ③ Important for cell volume control. ④ The sodium gradient created by this pump is used for secondary active transport.

Figure Process of primary active transport.
Na+ more concentrated K+ more concentrated

Figure Osmotic pressure and water movement.

Figure Sodium and volume of cell.
Extracellular fluid Intracellular fluid Sodium ion Water Figure Sodium and volume of cell.

Protein-mediated transport Secondary active transport sodium-coupled secondary active transport: ① ATP is not used directly. ② Depends on primary active transport mechanisms to create a concentration gradient. ③ Movement of sodium is always downhill, while the movement of actively transported solute on the same transporter is uphill. ④ There are symport( in the same direction as sodium) and antiport( in the opposite direction).

Figure Secondary active transport.

Flash Secondary active transport.
Na+ K+ ATP ADP pump cell Na+ G Cotransport Countertransport H+ Flash Secondary active transport.

Figure Transport of substances throng membrane.

Endocytosis and Exocytosis Very large molecules or particles enter or leave the cell by a specialized function of the cell membrane called endocytosis or exocytosis respectively. Endocytosis Principle form: ① Phagocytosis: only certain cell show the capability. ② Pinocytosis: ① most cell show the capability; ② the only way of large molecules such as protein entering the cell.

Figure Process of phagocytosis.
The membrane may be internalized? Figure Process of phagocytosis.

Flash Process of pinocytosis.

Receptor-mediated Endocytosis:
The cell membrane is not internalized, because the membrane is replaced by vesicle membrane at about the same rate( recycled). Receptor-mediated Endocytosis:

Endocytosis and Exocytosis Exocytosis ① Exocytosis provides a route by which membrane impermeable molecules such as protein synthesized by cells can be secreted into extracellular fluid. ② Examples : peptide hormone secretion, neurotransmitter release and so on. ③ It is always triggered by stimuli that open calcium channels in most cells.

Figure Process of exocytosis.
Exterior Plasma membrane Interior ③ Vesicle Golgi apparatus ② ① Endoplasmic reticulum Figure Process of exocytosis.

Flash Process of exocytosis.

SUMMARY ⑴ Structure of Cell Membrane and Membrane Transport
Membranous structure. Transport of substance through the cell membrane. ① Simple diffusion. ② Protein-Mediated transport. Facilitated diffusion and active transport. ③ Endocytosis and exocytosis.

protein External fluid Internal fluid
Much of intercellular communication is mediated by chemical messengers. Lipid insoluble messenger Lipid soluble messenger External fluid Receptor protein Internal fluid Hypothesis: Maybe some kind of protein can help lipid insoluble messenger to transmit its signal and cause subsequent response.

Figure Two kinds of route of signal transduction.

Figure Membrane Receptor Classes.

⑵ Signal Transduction of Cell Membrane
Signal transduction mediated by G-protein linked receptor. Signal transduction mediated by ionotropic receptor. Signal transduction mediated by enzyme-linked receptor.

Signal Transduction Mediated by G-protein Linked Receptor
Signal molecules involved in the signal transduction. G-protein linked receptor; G protein; G-protein effector; second messenger. Two import pathways of signal transduction mediated by G-protein-linked receptor. ① Receptor-G-protein-AC pathway. ② Receptor-G-protein-PLC pathway.

metabotrophic channel
G-protein coupled receptor metabotrophic channel outside inside Ligand( first messenger) GTP Responses Second messenger Figure Process of Signal transduction.

Response produces Signal molecule First messenger The process of signal transduction mediated by G-protein-linked receptor: G protein-linked receptor binds to G protein activates G protein effector activates G-protein linked receptor; G protein; G-protein effector; second messenger. Second messenger produces Target protein alters

Figure G-protein-linked receptor and G protein.

Signal molecules involved in the signal transduction. ① G-protein linked receptor: 7-trasmembrane receptor. ② G protein: bound to the receptor is a protein complex located on the inner surface of the plasma membrane and belonging to the family of heterotrimeric proteins and containing αβγsubunits. ③ G protein effector: AC; PLC; GC. ④ Second messenger: Substance that enter or are generated in the cytoplasm as a result of receptor activation by the first messengers. cAMP; IP3; DG; cGMP, Calcium ions are all second messenger.

Two import pathways of signal transduction mediated by G-protein-linked receptor. ① Receptor-G-protein-AC pathway. ② Receptor-G-protein-PLC pathway.

Figure Receptor-G protein-AC pathway.

Figure Receptor-G protein-PLC pathway.

Figure Contrast of two pathways.
ligand G-protein-linked receptor Figure Contrast of two pathways.

Signal Transduction Mediated by Ionotropic Receptor
The protein that acts as the receptor itself constitutes an ion channel. Process ① Ligand binds to ionotropic receptor. ② Ionotropic receptor is activated and the channel opens. ③ Ions flow across membrane which causes the change in the membrane potentail.

Figure Signal transduction mediated by ionotropic receptor.
Ligand-gated channal Ionotrophic channel Response: change in membrane potential. Figure Signal transduction mediated by ionotropic receptor.

Signal Transduction Mediated by Enzyme-Linked Receptor
① The receptors itself have intrinsic enzyme activity. ② There are two important receptors: tyrosine kinase receptor and guanylyl cylase receptor. Tyrosine kinase receptor Guanylyl cylase receptor

Figure Tyrosine kinase receptor .
Enzyme-linked receptor Receptor portion Enzyme portion Figure Tyrosine kinase receptor .

Figure Guanylyl cyclase receptor .
ANP Guanylyl cyclase receptor

Figure Review of signal transduction.

Figure Summary of signal transduction.

SMMURY ⑵ Signal Transduction of Cell Membrane
Signal transduction mediated by G-protein linked receptor. Signal transduction mediated by ionotropic receptor. Signal transduction mediated by enzyme-linked receptor.

⑶ Membrane Potentials and Action Potentials
Resting potential and its origin Action potential and its origin Excitation and excitability of tissues

Resting Potential and Its Origin
Waveform of the resting potential. Origin of the resting potential.

Nerve fiber RP Figure Measurement of resting potential. 0 mV -60mV
Experiment electrode outside inside Voltmeter 0 mV -60mV RP Intracellular recording indifferent recording Nerve fiber Figure Measurement of resting potential.

Waveform of the resting potential Resting potential All cells under resting conditions have a potential difference across their plasma membrane with inside of the cell negatively charged with respect to the outside. This potential is the resting membrane potential. The magnitude of the resting potential varies from -100 to -5mV depending upon the type of cell. Polarization The steady potential difference with the inside of the cell negatively charged with respect to the outside under resting conditions is also called polarization. How resting potential come into being ( how the potential difference is established )?

Figure Distribution of ions in the two sides of the membrane.
Indifferent electrode Recording electrode Figure Distribution of ions in the two sides of the membrane. Movement of ions across the membrane causes the potential difference.

Origin of the resting potential Movement of ions across the membrane cause the potential difference. Concentration difference and permeability of ions determine which kind of ions can pass through the membrane and the direction of the movement. The magnitude of resting potential is determined by two factors: ① Differences in specific ion concentrations in the intracellular and extracellular fluids. ② Differences in membrane permeabilities to the different ions.

membrane 20K+ 1K+ + + + + + + + + + + + + + + + + + + + + + + + + + +
inside outside 20K+ 1K+ + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + Figure Concentration difference and permeability of ions.

Figure Concentration difference across the membrane.
9:1 20 400 440 50 560 52 2 0.0002 -75 +55 -60 Squid axon Figure Concentration difference across the membrane.

Cl- K+ Ca2+ Na+ Cl- K+ Organic anions Ca2+ Na+
Inside outside Cl- Cl- K+ K+ Organic anions Ca2+ Ca2+ Na+ Na+ Figure Distribution of ions in the two sides of the membrane.

Resting Potential and its Origin
Origin of the resting potential Large organic anions and Ca2+ are impermeable to the membrane, so the ions that can pass through the membrane is likely : K+ ,Na+, Cl- . SO K+ and Na+ and Cl- may play an important role in the origin of resting potential. Hypothesis: Only K+ is permeable to the membrane. What will happen?

There are two driving force for ions diffusion:
① Concentration difference. ② Electrical potential difference. Electrochemical driving force Concentration difference make K+ move from the inside of the membrane to the outside. Electrical potential difference caused by diffusion of K+ prevent K+ from moving into the outside. Chemical driving force = electrical driving force. The electrochemical driving force is zero. The membrane potential in this state is called K+ equilibrium potential( Ek ).

Flash How the K + equilibrium potential is established.
Concentration difference driving force Electrical difference driving force = Nerve fiber inside outside 1K+ 20K+ + - K+ equilibrium potential The net flux is zero Flash How the K + equilibrium potential is established. How the K + equilibrium potential is calculated?

Origin of the resting potential Nernst equation Nernst equation describes the equilibrium potential for any ion species. Ek= RT zF In 〔K+〕 i o (mV) = -75mV (Squid axon) ≈ RP(-60mV) So the origin of resting potential is not only caused by the movement of potassium. Hypothesis is not right.

Origin of the resting potential Chord conductance equation Em= gK ∑g EK gNa ENa gCl ECl + ∑g=gK+gNa+gCl The greater the membrane permeability to an ion species, the greater the contribution that ion species will make to the membrane potential. ECl=RP gK>>gNa=0 EK≈RP

EK = ﹥ RP Membrane Inside Outside 20k+ k+ + - + - - + - + - + Na+ 9Na+
Flash Contribution of sodium diffusion to the resting potential. Who maintain the concentration difference?

+ Figure Contribution of sodium potassium pump to resting potential.
Sodium potassium pump causes a continuous loss of positive charges from inside membrane.

Origin of the resting potential K + move from inside of the cell to the outside under resting condition, which causes the inside of the cell negatively charged with respect to the outside. It is the main factor of the origin of the resting potential. Under resting condition, few Na+ diffuse from outside of the cell to the inside, which also contribute to the origin of the resting potential. Sodium-potassium pump results in the net transfer of positive charge to the outside of the cell, so sodium-potassium also contributes to the origin of the resting potential.

Action Potential and its Origin
Waveform of the typical action potential. Mechanism of the action potential. Ionic basis of the action potential. Propagation of the action potential.

Figure Measurement of action potential. AP 0mV
Experiment Indifferent electrode Recording electrode Voltmeter AP 0mV RP Nerve fiber stimulator

Figure Waveform of the typical action potential.
depolarization repolarization Spike potential hyperpolarization After hyperpolarized wave polarization Figure Waveform of the typical action potential.

Waveform of the typical action potential. Terms Polarization: The resting potential state is called polarization. Depolarization: The membrane potential is less negative than the resting potential. Repolarization: When a membrane potential that has been depolarized returns toward the resting value, it is called repolarization. Hyerpolarization: When a membrane potential is more negative than the resting level, it is called hyperpolarization. Overshoot: Overshoot refers to a reversal of the membrane potential, in other words, the inside of a cell becomes positive relative to the outside.

Membrane potential (mV)
-70 -55 +35 Membrane potential (mV) overshoot depolarization repolarization hyperpolarization Time（ms）

Waveform of the typical action potential. Action potential Definition When such cells as neurons are stimulated, there will be rapid and large alterations in the membrane potential, which undergo a process of depolarization, repolarization and then returning to the resting potential. This process is called action potential. Shape Rising phase Falling phase After hyperpolarized wave Sharp spike Spike potential (Major sign of action potential)

Mechanism of the action potential. ① As the origin of the resting potential, the changes in membrane potential occur because of change in the permeability of the membrane to ions. ② The action potential is initiated by a transient change in membrane ion permeability, which allows sodium and potassium ions to move down their concentration gradients.

Ionic basis of the action potential. Rising phase Depolarization of membrane Voltage-gated sodium channels open Stimulus More Sodium ions move into the cell Membrane becomes more depolarized Threshold potential is reached More sodium channels open The inside positively charged Membrane potential overshoots

9Na+ Membrane ++++++ ------ ++++++ ------ - + + - -- ++
Outside Inside ++++++ ------ ++++++ ------ Resting potential -70 Sodium equilibrium potential 30 - + + - -55 9Na+ Na+ -- ++ Stimulus Resting potential

Ionic basis of the action potential Falling phase Sodium permeability abruptly decreases and voltage-gated potassium channels open, which makes the membrane potential begins to repolarize rapidly to its resting potential. After hyperpolarized wave After sodium channels have closed, some of the voltage-gated potassium channel still open, which causes the after hyperpolarized wave.

20K+ Membrane K+ --- +++ --- +++ Outside Inside Resting potential -70
30 K+ 20K+ +++ --- +++ ---

Figure Graded potential and action potential.
acting potential local response Figure Graded potential and action potential.

Graded potential Definition Graded potential( local response) are changes in membrane potential that are confined to a relatively small region of the plasma membrane. Characteristics ① Electrotonic propagation. ② Summation. ③ Graded magnitude.

Figure Electrotonic propagation of the graded potential.

Figure Summation of the graded potential.

Figure Graded magnitude of the graded potential.

Initiation of the action potential An action potential will not occur until the initial rise in membrane potential is great enough to create the positive feedback cycle of sodium channel, that is to say, to reach the threshold potential.

Threshold potential Experiment Action potential Definition:
-70 Experiment Threshold potential Action potential Definition: The threshold potential is the membrane potential to which a membrane must be depolarized to initiate an action potential. Threshold potential -55 膜电位（mV） Graded potential Characteristics: ① Create the positive feedback cycle of sodium channel. RP ② From this moment on, the membrane events are independent of the initial stimulus. Stimulus

Propagation of the action potential Mechanism The potential difference between the depolarized areas of the membrane and adjacent resting membrane areas causes ions to flow, that is to say, the potential difference creates local currents, which causes the propagation of the action potential. Characteristics ① Action potential propagate in both directions. ② Action potentials are not conducted decrementally. ③ The propagation follows the all-or-none principle. ④ The velocity depends upon fiber diameter( larger diameter faster) and whether or not the fiber is myelinated( myelinated fiber faster).

Figure Propagation of the action potential.
Local currents + - + - + - + - - + - + - + + - + - + - + - + - + - + - Nerve fiber Figure Propagation of the action potential.

Figure Propagation of the action potential.

Figure Contrast of propagation in nonmyelinated and myelinated axon (Saltatory Conduction).

Contrast of action potential and graded potential Action potential Graded potential Magnitude Large Small Summation All-or-none propagation Electrotonic propagation Unattenuated propagation

Excitation and Excitability of Tissues
Excitation and excitable cells and excitability Excitation Excitation is used to describe responses of a cell to stimuli. It has almost the same meanings as the action potential or the process that action potential produced. Excitable cells ① Nerve cells. ② Muscle cells. ③ endocrine cells. ④ immune cells. ⑤ reproductive cells.

Excitation and excitable cells and excitability. Excitability The ability to generate action potential is known as excitability. Excitability and threshold stimulus Stimulus parameters: Intensity; duration; rate of change. Threshold intensity: The minimal intensity of stimulus to cause action potential of cells is called threshold intensity. This stimulus is called threshold stimulus. Subthreshold stimulus: the Stimulus is lower than threshold.

Excitation and excitable cells and excitability Excitability and threshold stimulus Suprathreshold stimulus: the Stimulus is higher than threshold. Both threshold and suprathreshold stimulus cause action potential. Relationship between threshold potential and threshold stimulus. Threshold potential is the membrane potential to which a membrane must be depolarized to initiate an action potential.

Excitation and excitable cells and excitability Relationship between threshold potential and threshold stimulus. Threshold stimulus are stimuli that are just strong enough to depolarize the membrane to the threshold potential. Threshold intensity or threshold stimulus is used as an index to evaluate the excitability. A series of excitability alteration after excitation Absolute refractory period: During action potential , a second stimulus, no matter how strong, will not produce a second action potential.

A series of excitability alteration after excitation Relative refractory period: During action potential , a second stimulus that is greater than usual can produce a second action potential. The refractory periods can: ① Limit the number of action potentials. ② contribute to the separation of these action potentials. ③ determine the direction of action potential propagation.

Figure The state of voltage-gated sodium ion channel.
Resting Open Inactive

Figure A series of excitability alteration after excitation.

SMMURY ⑶ Membrane Potentials and Action Potentials
Resting potential and its origin Action potential and its origin Excitation and excitability of tissues

Contraction of Muscle Instructor: Zhu Su Hong Department of Physiology
Jining medical college Office: 0850 physiological sciences

Functions of muscle contraction
1.Produce movement and Stabilize body positions 2. Regulate organ volume 3.Generate heat

Characteristics of muscle tissue
1.Excitability – the ability to receive and respond to a stimulus (a neurotransmitter) 2.Contractility – the ability to contract or shorten 3.Extensibility – the ability to be extended or stretched 4.Elasticity – the ability to recoil and resume the original resting length after being stretched

Three Muscle Types Muscle accounts for nearly half of the body’s mass - Muscles have the ability to change chemical energy (ATP) into mechanical energy Three types of Muscle Tissue – differ in structure location, means of activation and function Skeletal Muscle Cardiac Muscle Smooth Muscle

General characteristics and functions of muscle
skeletal striated voluntary Producing movement and heat cardiac lightly striated involuntary Providing power for blood circulation smooth non-striated regulation of the internal enviroment

How can STRIATED muscles contract?

How Can SKELETAL Muscles Contract ?
1.Being stimulated by a motor neuron 2.Transmission of excitation at neuromuscular junction 3.Excitation–contraction coupling 4.Myofilament sliding

Being stimulated by a motor neuron
The Motor Unit

How do STRIATED muscles contract?

Transmission of excitation at neuromuscular junction
1. Physiologic Anatomy of the Neuromuscular Junction 2. Major Processes of Excitation Transmission at Neuromuscular Junction 3.Destruction of the Released Acetylcholine by ACE 4.Disruction of Neuromuscular Signaling

The Neuromuscular Junction

The Structure of Neuromuscular Junction
Enlarge view of the neuromuscular junction

The Structure of Neuromuscular Junction
The neuromuscular junction be made of: prejunctional membrane=the axon terminal junctional cleft=synaptic cleft postjunctional membrane=the motor end plate

When a nerve impulse reaches the neuromuscular junction: 1.Voltage-regulated calcium channels in the axon membrane open and allow Ca2+ to enter the axon 2. Ca2+ inside the axon terminal causes some of the synaptic vesicles to fuse with the axon membrane and release ACh into the synaptic cleft (exocytosis). 3.ACh diffuses across the synaptic cleft and attaches to Ache receptors on the motor end-plate and Na+/K+ channel is opened when ACh binding to receptors. 4. EPP is produced on the motor end-plate when Na+ Diffusing into the cell. 5.An action potential is generated adjacent the motor end- plate and propagated across the sarcolemma.

Calcium channels open and Ca2+ diffusing into the cell

Synaptic vesicles fuse with the axon membrane and release ACh into the synaptic cleft

ACh attaching to receptors on the motor end-plate and Na+/K+ channels is open and Na+﹑K+ move cross the membrane

Generation and Propagation of an Action Potential
The sarcolemma, like other plasma membranes is polarized. There is a potential difference (voltage) across the membrane When Ach binds to its receptors on the motor end plate, chemically (ligand) gated ion channels in the receptors open and allow Na+ and K+ to move across the membrane, resulting in a transient change in membrane potential - Depolarization End plate potential - a local depolarization that creates and spreads an action potential across the sarcolemma

The inside of the sarcolemma is negative relative to the outside The predominant extracellular ion is Na+ and the predominant intracellular ion is K+ (maintained by Na+- K+ ATPase) The difference in charge is the resting membrane potential (voltage) The sarcolemma is relatively impermeable to both ions

The axon terminal of a motor neuron releases ACh. ACh-receptor binding at the motor end plate results in production of an end plate potential as large number of Na+ diffuses into the cell. The resting membrane potential is decreased (local depolarization)。This is called EPP. ↑ Na+ Stimulus Although the EPP can not produce the action potential on the end-plate. because of lacking of voltage-gated sodium channels on the end-plate.

The EPP will travel in local current. The motor end plate potential may cause adjacent areas of the sarcolemma to become permeable to Na+ (voltage-gated sodium channels open) and adjacent areas of the sarcolemma depolarize as sodium follows its electrochemical gradient.So the action potential is generated and then travels over the sarcolemma. Once initiated, the action potential is unstoppable, and ultimately results in the contraction of a muscle.

voltage-gated sodium channels open

Repolarization Immediately after the depolarization wave passes, the sarcolemma permeability changes. Na+ channels close and voltage-gated K+ channels open. K+ diffuses out of the cell, restoring the electrical polarity (but not the ionic conditions) of the resting state sarcolemma.

The Ach once released into the synaptic
cleft continues binding to its receptors. However at the same time most of ACh is destroyed by ACE. ACh is hydrolyzed by ACE Into choline and acetate.So Ach terminates it function as a transmitter molecule. And the Membrane permeability returns to the resting state. The choline portion is taken up by the prejunctionary membrane for resynthesis of Ach and the acetate diffuses away into the extracellular fluid.

There is no Ach in the synaptic cleft,
there is no action potential produced. So the skeletal muscle stops contracting. The skeletal muscle is stimulated only once, the skeletal contracts only once!

Processes of Excitation Transmission at NMJ

Summary Why? The muscle contraction is generated
1.The action potential travelles along the nerve fiber and arrives at the axon terminal 2.Voltage-regulated Ca2+ channels open and Ca2+ enter into the axon 3.Synaptic vesicles fuses with the axon terminal and release ACh into the cleft 4.Binding ACh to receptors on the end-plate opens Na+/K+ channel 5.The EPP is produced on the end-plate 6.The action potential is generated and propagated along sarcolemma Why? The muscle contraction is generated

Why the action potential on the sarcolemma lead to the muscle contraction?

How Can SKELETAL Muscles Contract ?

Muscles structure provides a key to understand the mechanism of striated muscle contraction!

Physiologic Anatomy of Striated muscle
a whole muscle consists of a large number of muscle fibers (cells) , plus connective tissue wrappings, blood vessels, and nerve fibers.

Skeletal Muscle – CT Sheaths
Three connective tissue sheaths: Epimysium : surrounding the entire muscle Perimysium : surrounding groups of muscle fibers (fascicles) Endomysium : surrounding each muscle fiber (cell) At each end of a muscle, the collagen fibers of the epimysium, perimysium, and endomysium come together to form a bundle of fibers called a tendon or a broad tendinous sheet called an aponeurosis.

Muscle fibers are the principal part of the muscle.

Microscopic Anatomy-Skeletal Muscle Fiber
Each fiber is a long, cylindrical cell with multiple nuclei just beneath the sarcolemma Fibers are 10 to 100 m in diameter, and up to 30 cm long Each cell is a syncytium produced by fusion of embryonic cells

Myofibrils account for about 80% of the cellular volume of a skeletal muscle fiber.They are the contractile elements of skeletal muscle fibers.

Mycroscopic Anatomy-Myofibrils
Within the myofibril, are thick and thin myofilaments. these myolfilaments are arranged in a regular pattern.The arrangement of myofibrils creates a series of repeating dark A bands and light I bands.

What’ the dark band ? What’ the light band?
How are the thick and thin filaments arranged into a regular pattern? What’ the dark band ? What’ the light band?

One unit of this repeating pattern is known as a sarcomere.
The thick and thin filaments in each myofibril are arranged in a repeating regular pattern along the length of the myofibril. One unit of this repeating pattern is known as a sarcomere.

A band extend the entire length of thick filaments.
The thick filaments are located in the middle of each sarcomere and there orderly parallel arrangement produces a wide ,dark band called the A band . sarcomere A band extend the entire length of thick filaments.

Each sarcomere contains two sets of thin
filaments.One at each end. One end of each thin filament is anchored to a network of interconnection proteins called the Z lines. While the other end overlaps a portion of the thick filaments. Between the two successive Z line is a sarcomere. Thin filaments from the two adjacent sarcomeres are anchored to the two sides of each Z line.

Thin filament Thick filament H zone M line sarcomere

Those portions of the thin filaments that do not overlap the thick filament appears light.We call those the I band. The I band lies between the end of A bands of two adjacent sarcomeres and contains the two adjacent thin filaments. The I band is anchored by the Z line.

In the central of the H band is a dark line called the M line.
The edges of the A band are darker in appearance than the centre region. The central lighter region of the A band is called the the H band. The H band thus contains only thick filaments that are not overlapped by thin filaments. sarcomere In the central of the H band is a dark line called the M line.

The M line is produced by proteins located at the centre of the thick filaments in a sarcomere.
The M lines serve to anchor the thick filaments,helping them stay together during contraction. sarcomere

T Tubule—SR System

T Tubules – (transverse)
T tubules at each A band - I band junction are continuous with the sarcolemma. The lumen of the tubule is continuous with the extracellular space. Conduct electrical impulses to the muscle (every sarcomere) - signals for the release of Ca2+ from adjacent terminal cisternae T tubule

Sarcoplasmic Reticulum (SR)
SR - an elaborate, smooth ER that surrounds each myofibril. It is composed of two major parts.(1) Long longitudinal tubules ;(2) Terminal Cisterns. SR regulates intracellular Ca2+ triad triad Terminal Cistern

Triad – 2 terminal cisternae and 1 T tubule
T tubules and SR provide tightly linked signals for muscle contraction T tubule proteins act as voltage sensors SR proteins are receptors that regulate Ca2+ release from the SR cistern

In order to comprehend the
filament sliding we also ought to study the structure of the filaments.

Thick Filaments The thick filaments are composed almost entirely of the contractile protein myosin.

Thin Filaments Thin filaments (F actin) are mostly composed of the protein actin. The regulatory protein- tropomyosin and troponin are bound to actin . On each actin molecular ,there is a myosin binding site where a cross-bridge can attach.

Arrangement of Filaments in a Sarcomere

Myofilament Sliding Theory
In the relaxed state, actin and myosin filaments do not fully overlap. With stimulation by the nervous system, myosin heads bind to actin and pull the thin filaments. Actin filaments then slide past the myosin filaments so that the actin and myosin filaments overlap to a greater degree (the actin filaments are moved toward the center of the sarcomere, Z lines become closer)

Sliding Filament Model of Contraction
Relaxed State

Partially Contracted

Fully Contracted

Myofilament Sliding theory
During shortening,the sarcomere is shortened, but there is no change in the length of either the thick or thin filaments.During shortening，there is only change in the length of light band and there is no change of dark band.

One stroke of a cross–bridge produces only a very small movement
One stroke of a cross–bridge produces only a very small movement .As long as a muscle fiber remains activated , each cross-bridge repeats its swiveling many times .It will lead to large displacements of the filaments.

When the filaments slide, the cross-bridge
will undergo four different states . We call it cross-bridge cycle. It is the integral process that the actin and myosin filaments slide.

Cross-bridge cycle Each cross-bridge cycle consists of four steps :
1.Attaching of myosin cross-bridge to the actin of thin filament. 2.Movement of the cross-bridge ,producing tension in the thin filament . 3.Detachment of the cross-bridge from the thin filament. 4.Energizing the cross-bridge so that it can again attach to a thin filament and repeats the cycle.

Cross-bridge cycle Step:1 Actin binding. A + M﹒ADP﹒Pi A ﹒M ﹒ADP﹒Pi

Cross-bridge cycle Step:2 Movement of cross-bridge.
A ﹒M ﹒ADP﹒Pi A ﹒M + ADP + Pi

During the cross-bridge movement myosin is bound to actin very firmly
During the cross-bridge movement myosin is bound to actin very firmly. This linkage must be broken in order to allow the cross-bridge to attach to another portion of the actin filament, as to make the thin filaments slide toward the center of the sarcomere.

Cross-bridge cycle Step:3 Dissociation of cross-bridge from actin.
A ﹒M + ATP A + M ﹒ATP In this step,ATP is not split.Here ATP is not acting as an energy source but only as an allosteric modulator of the myosin.So it can weaken the binding of myosin to actin.

Cross-bridge cycle Step:4 ATP hydrolysis A + M ﹒ATP A + M ﹒ADP﹒Pi
Following the dissociation of myosin from actin ,the ATP bound to myosin is hydrolysis, thereby reforming the energized state of myosin with ADP and Pi binding to the cross-bridge again.

Cross-bridge cycle

The cross-bridge cycle repeats as long as ATP is
available and the Ca2+ level near the thin filament is high. We can see that the Ca2+ plays an important role in the cross-bridge cycle, it can start and stop the filaments sliding. Why does the high level of Ca2+ in the cytoplasm initiate the energized cross-bridge attaching to actin? Let us study the Ca2+ and the contraction mechanism.

Thin Filament Regulatory Proteins
Two Tropomyosin strands spiral around the actin filament and block the myosin-binding sites in a relaxed muscle fiber Troponin is a three-polypeptide complex: TnI - Inhibitory subunit that binds to actin TnT - binds to Tropomyosin TnC - binds to Calcium ions

Ca2+ and the Contraction Mechanism
At low intracellular Ca2+, tropomyosin blocks the binding sites on actin and myosin cannot attach – this is the relaxed state.

As Ca2+ levels rise, ions bind to troponin regulatory sites. Calcium-activated troponin binds an additional two Ca2+ at a separate regulatory site.

Calcium-activated troponin undergoes a conformational change. This change moves tropomyosin away from actin’s binding sites.

Displacement of the tropomyosin allows the myosin head to bind to the actin and the cross-bridge cycle of contraction begins

How can the high level of Ca2+ in the cytoplasm be available?
The change of Calcium level is controlled by electrical events in the muscle plasma membrane. This is Excitation-contraction coupling.

Excitation-Contraction Coupling
1.Definition: E-C Coupling is the sequence of events linking the transmission of an action potential along the sarcolemma to muscle contraction (the sliding of myofilaments). triad 2.position: at the triad 3. the process

The process of Excitation-Contraction Coupling
The action potential is propagated along (across) the sarcolemma and travels through the T tubules At the triads, the action potential causes voltage sensitive T tubule proteins to change shape.This change, in turn, causes the SR proteins of the terminal cisterns to change shape, Ca2+ channels are opened and Ca2+ is released into the sarcoplasm from the terminal cisterns.(where the myofilaments are)

Some of the Ca2+ binds to troponin, troponin changes shape and causes tropomyosin to move which exposes the active binding sites on actin. Myosin heads can now alternately attach and detach, pulling the actin filaments toward the center of the sarcomere. (ATP hydrolysis is necessary)

The short calcium influx ends (30 ms after the action potential ends) and Ca2+ levels fall. An ATP-dependent Ca2+ pump is continually moving Ca2+ back into the SR. Tropomyosin blockage of the actin binding sites is reestablished as Ca2+ levels drop. Cross-bridge activity ends and relaxation occurs

Excitation-Contraction Coupling
Action potential in the T-tubules causes the release of Ca2+ from the SR. This process is known as E-C Coupling.

Summary: how can the skeletal muscle contract ?

Performance of Contraction
The muscular performance of contraction includes: 1.the muscular tension 2.the muscular shortening 3.the velocity of change of the tension and shortening during the contraction

the muscular tension （1）Definition: the force exerted on an object by
a contracting muscle is known as muscular tention. It must be distinguished from the load. Load: the force exerted on the muscle by an object (usually its weight). （2）Isotonic contraction: a muscle contraction is said to be isotonic contraction when it shorts with the tension remain constant.

the muscular shortening
Isometric contraction Definition: when a muscle develops tension but does not shorten(or lengthen), the contraction is said to be isometric contraction. Such contractions occur when the muscle supports a load in a constant position or attempts to move an otherwise supported load that is greater than the tension developed by the muscle. For example holding a dumbbell at a constant position requires muscle contraction but not muscle shortening.

be influenced by (2) afterload (3) contractility
The performance of contraction can be influenced by (1) preload (2) afterload (3) contractility (4) summation of the contractions

Preload (Length-force relationship)
(1)Definition: the force on the muscle prior to contraction.It sets the initial length of the muscle. At any given length ,if the muscle is stimulated to cause isometric contraction,it will develop an additional amount of tension(active tension), which is a function of the initial fiber length. while the passive tension is directly related to the extent to which a muscle is stretched. (2) Effect of preload on force of contraction (Length-force relationship)

Length-force relationship
As the preload increases, the resting length of the muscle increases and the ability of the muscle to develop tension and shorten increases, with limits. Therefore ,there is an optimal length at which peak tension will be developed. At lengths shorter or longer than this, developed tension (active) decreased. The relationship can be partially explained in terms of the filaments sliding mechanism.

D Length-tension diagram for a single sarcomere shows maximum strength of contraction when the sarcomere is 2.0 to 2.2 micromeres in length.At the upper right are shown the relative positions of the actin and myosin filaments at different sarcomere length from point A to point D.

Stretching a fiber to about the length of D point, pulls the filaments apart so that there is no overlap.At this point there can be no cross-bridge binding to actin so no development of tension. Between D and C more and more filaments overlap, and the tension is produced in proportion to the increased number of cross-bridges in the overlap region At point B and C all the cross-bridges can bind to the actin filaments, thereby producing maximal tension. At lengths less than B,the tension declines. D

Afterload (1)Definition: the afterload is the force on the
muscle during the contraction. The afterload determines the work that the muscle must do. (2) Effect of Afterload on Muscle Contraction (Force-Velocity Relationship) In general ,the lighter the afterload, the faster the muscle shortens and the more it shortens. As the afterload is increased, the velocity of shortening and the amount of shortening decrease.

Force-Velocity Relationship
The shortening velocity is maximal when there is no load and is zero when the load is equal to the maximal isometric tension.If the afterload is greater than the muscle can lift, the muscle develops tension without shortening external. Relation of load to velocity of contraction in a skeletal muscle

Contractility The muscle contractility refers to the inherent strength of the muscle and is independence of loads. It is determined by calcium levels in the sarcoplasm and myosin ATPase activity.

Force summation Summation occurs in two ways:
(1)by Increasing the number of motor units which is called Multiple Fiber Summation. (2)By increasing the frequency of stimulation which is called Frequency summation.

A twitch 1.Definition: the mechanical response of a single contraction to a single action potential is known as a twitch. 2.There are there phases (1) latent period (2) period of contraction (3) period of relaxation

Three phases of muscle contraction
Following the action potential, there is an interval of a few milliseconds before the muscle begins to contract, known as the latent period. The time from the beginning of tension development at the end of the latent period to the peak tension is the contraction period. The relaxation period follows the contraction period and is the result of Ca2+ ion concentration returning to normal levels。

Three phases of muscle contraction
The curve of the twitch of a skeletal muscle

Since a single action potential in a skeletal
muscle fiber lasts 1 to 2ms but the twitch may last 100ms,it is possible for a second action potential to be initiated during the period of contraction or relaxation. The increase in muscle tension from successive action potentials occurring during the phase of mechanical activity is known as summation. A maintained contraction in response to repetitive stimulation is known as tetanus.

Frequency Summation 1. Incomplete tetanus 2. Complete tetanus

Incomplete tetanus 1.Definition: Each new contraction occurs before the previous one is over (The second contraction is added partially to the first). 2.Characteristics: the relaxation phase is becoming shorter and shorter. twitch Incomplete tetanus complete tetanus

Complete tetanus 1.Definition: The successive contraction are so
close that they fuse together and appears to be completely smooth and continuous. 2.Characteristics:the relaxation phase is disappear. twitch Incomplete tetanus complete tetanus

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