Excitable Tissues.pptx

Excitable tissues-
Nerve and Muscle
1

Terms:
• Ion
– Atom/molecule that have an electrical charge.
• Anion
– Negatively charged ion (e.g., Cl−).
• Cation
– Positively charged ion (e.g., Na+, K+, Ca2+).
• Influx of ions
– Flow of ions into the cell.
• Efflux of ions
– Flow of ions out of the cell.
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Membrane Potential
Def.  electrical energy difference between the
inside and outside of the cell.
• Em = Vin – Vout, where
Vin = Potential on the inside of the cell
Vout = Potential on the outside
Em = Membrane potential (mV)
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• All cells have membrane potential.
• Membrane potential is due to charge separation across the
membrane.
• The Range of Em: -20 mV to -90mV (organism, cell type).
• Any change of a membrane’s permeability of ions causes a
change in membrane potential.
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• Resting Membrane Potential:
• Steady transmembrane potential of a cell that is not
producing an electrical signal.
• No net flow of ions across the plasma membrane.
(No net inward current)
– All cells have RMP.
o Nerve, cardiac and skeletal muscle: -55 to -90mV
o Smooth muscle: -55 to -30mV
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• RMP is necessary for the cell to fire an action potential,
AP.
• Nerve and muscle cells are capable of generating
rapidly changing electrochemical impulses at their
membranes, and these impulses are used to transmit
signals along the nerve or muscle membranes.
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• Determinants of Em:
1. Passive determinants
2. Active determinant
1. Passive Determinants
a. Biochemical nature of plasma membrane of the cell.
- Lipid bilayer (7nm ): Selective permeability
• Extracellular: +VE
• Intracellular: - VE
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b. Asymmetrical/Unequal distribution of ions
across the membrane
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Concentration of ions
Electrostatic
Inside Outside [ ] gradient pressure
• Sodium (Na+) 12mM 145mM into cell into cell
• Potassium (K+) 150mM 5mM out of cell into cell
• Chloride (Cl-) 9mM 125mM into out of
• Calcium (Ca2+) 10-4mM 2.5mM into cell into cell
• Organic anions: Fixed anions (Proteins, nucleotides, polyphosphates…)
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c. Leakage(Leak, non-gated, passive) channels
• Leak K+ channels, leak Na+ channels, leak Cl- channels
• Leakage K+ channels are open at resting potential more
than Na+, Cl-
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2. Active Determinant:
– Na+-K+-ATPase (Na+-K+ pump)
i. Features:
a. A carrier molecule uses the membrane-bound ATPase.
b. Primary active transport process (consumes ATP, pumps
against conc. or electrical gradient).
c. Operates as antiporter (coupled transporter):
• Pumping 3Na+ out of the cell
• Pumping 2K+ in (Electrogenic pump).
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ii. Functions
i. Maintenance of gradient of Na+ and K+ across the
cell membrane
• Controls cell volume ( Na+ regulating osmotic
forces)
ii. Control of membrane potential and excitability.
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Cellular Signaling:
• All body cells display a membrane potential
• Nerve and muscles are excitable tissues.
o They can undergo transient, rapid fluctuations in their membrane
potentials, which serve as electrical signals when excited.
 Change in membrane potential (ΔEm) ) is the basis for signaling in the
nervous system.
 Neurons use these electrical signals to receive, process, initiate, and
transmit messages.
 In muscle cells, these electrical signals initiate contraction.
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Mechanism of signaling:
• Stimulus (physical, mechanical, chemical, electrical…)

Sensory receptors

Transform stimulus energy /Transduction

Ion channels open

Inward flow of current (Na+)

Depolarization  ΔEm

Receptor potential /graded potential

Action Potential

CNS ...→ RESPONSE.
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There are two basic forms of electrical signals
1. Graded potentials, which serve as short-distance
signals.
2. Action potentials; which signal over long distances.
1. Graded potentials:
– Local membrane potentials changes occuring in varying grades
of magnitude or strength.
– die out over short distances.
– Can initiate action potential
– No refractory period
E.g. End plate potential, pacemaker potential...post synaptic
potential…
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2. Action Potentials
• Def:  rapid, transient(short lasting) reversal in the electrical
polarity of the excitable cells.
• self-propagating electrical excitation in the plasma membrane
of excitable cells which conduct down the length of the fiber.
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•Sequential opening of voltage-gated channels of Na+ and K+
initiates and terminates the action potential.

Phases and Ionic Basis of Action Potential:
1. Threshold Potential:
– Minimum value of Em at which an action potential
will occur.
– Initiated by rapid opening of fast Na+ channels.
– AP occurs only when the NET inward movement of
positive charge happened (gNa
+ > gK
+ or Na+ influx >
K+ efflux).
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• Magnitude is 15mV (R=10-20mV) (-70mV  -
55mV).
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2. Depolarization Phase/ upstroke
• ↑gNa
+  flow of Na+ into the cell
• Membrane suddenly becomes permeable to sodium
ions
• The normal “polarized” state of −90 millivolts is
immediately neutralized with the potential rising
rapidly in the positive direction.
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3. Overshoot / peak of the action potential
i. Portion of the AP during which the membrane potential
is positive.
ii. Magnitude: 0 to +30 or to +40mV
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4. Repolarization / Downstroke
•Rapid return of the membrane towards its RMP.
•↑gK+ (delayed opening of K+ channels )
•Time-limited nature of Na+ permeability(closure of
Na+ channels).
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5. After hyperpolarization.
• Membrane potential becomes more negative
than its RMP at the end of the action potential.
• Further outward movement of K+ through still-
open K+ channel.
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Refractoriness/Refractory period
i. Def.  an interval during which it is more difficult to elicit
another action potential before the membrane polarity is in its
resting state .
• Types:
a. Absolute refractory period
b. Relative refractory period
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a. Absolute Refractory Period:
• Another AP can not be elicited, regardless of the
strength of the stimulus.
• Begins at the start of the upstroke and extends into the
down stroke.
• During this period membrane cannot be excited
again.
b. Relative Refractory Period
• A second AP can be elicited if the stimulus is adequate.
• Stimulus must be greater than normal (suprathreshold).
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• Rationale:
i. Ensures ONLY one-way of propagation of APs along
an axon.
ii. Imposes a limit on the maximum rate a neuron can
fire.
iii. Prevents APs from summating.
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Features of action potential:
1. All-or-none phenomenon.
2. Has threshold.
3. Amplitude and duration is κ
4. Always depolarizing.
5. Has refractory period.
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All or None?
• Once threshold intensity is reached, a full action potential is
produced.
• Threshold is a critical all-or-none point.
• The action potential fails to occur if the stimulus is subthreshold
in magnitude.
– It happens completely or it does not occur at all.
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Propagation of Action Potential/ Signal
Transmission in Nerve
• Types:
i. Cable conduction/Continuous conduction;
- involves the spread of the action potential along
every patch of membrane down the length of the axon.
- Occurs in unmylinated nerve
- Speed of AP is slow
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ii. Saltatory Conduction
- Occurs in myelinated nerve
- Fast conduction
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Action Potentials with Plateau
• This type of action potential occurs in heart muscle
fibers,
• The plateau prolongs the period of depolarization and
causes prolonged contraction of heart muscle.
• Causes of the plateau
1.Two types of channels are involved in the
depolarization process in cardiac muscle cells:
A. fast channels (sodium channels) and
B. “slow” L-type Ca2+ channels
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Action potential in contractile cardiac muscle cells:
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 Opening of fast channels causes the spike portion of
the action potential, whereas
• The slow, prolonged opening of the slow calcium
channels which allows calcium ions to enter the fiber,
which is largely responsible for the plateau portion of
the action potential as well.
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Nerve cell
 The nervous system is composed of two principal types of
cells - neurons and supporting cells (neuroglia/glial Cells).
 Neurons are the basic structural and functional units of the
NS.
 They are specialized to respond to physical and chemical
stimuli, conduct electrochemical impulses, and release
chemical regulators(NTs).
 Through these activities, neurons enable the perception of
sensory stimuli, learning, memory, and the control of muscles
and glands.
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Major functions of neurons
i. Impulse reception:
 Internal environment
 External environment
(Special senses)
ii. Impulse conduction: in the form of APs + Graded
potential
iii. Impulse transmission:
Chemical
Electrical
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Cellular Structures and Function of a Neuron
a. Soma
b. Dendrites
c. Axon
d. Presynaptic Terminal

a. The Soma (Cell Body)
i. Is the enlarged portion of the neuron that
contains the nucleus
ii. Gives rise to axon and dendrites.
ii. Has nucleus, nucleolus, mitochondria, RER
+GA …
iii. Cytoskeletal elements: microtubules
microfilaments
iv. Functions:
a. Metabolic center of the neuron
• Membrane constituents.
• Enzymes
• Neurotransmitters etc. are synthesized
b. Reception + integration of incoming signals 46

b. Dendrites
i. Origin: apical or basal
ii. Components:
• Voltage-gated Ca2+-Channels
• Voltage-gated Na+ Channels
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iii. Functions:
a) Receive the input signal from other neurons.
• 90% surface area (Synaptic contacts:104 - 4
x105)
• Intelligence Vs. mental retardation (depends
on the number of synapses) .
b). Computation or integration of the signal.

c. Axon
i. Origin: soma, ONLY ONE.
ii. Components: SER, prominent cytoskeleton, Mitochondria
(Lacks RER, free ribosomes and GA)
i. Special features:
• Axon hillock
• Myelin sheath
• Nodes of Ranvier
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iv. Functions:
a. Initiation of action potential at the axon hillock.
High density of voltage-gated ion channels of Na+, K+ , Ca2+
threshold (-45mV)
b. Impulse conduction in the form of action potential
(6-120m/s)
c. Axoplasmic transport
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d. Synaptic Terminals/Synaptic buttons
i. Transmitting elements of the neuron (Synaptic vesicles, and
high number of mitochondria)
ii. The cell sending out information Presynaptic cell
iii. The cell receiving the information Postsynaptic cell
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Fig. Synaptic
terminal

iv. If termination of presynaptic neuron:
• On dendritic spine of postsynaptic neuron Excitatory (90%)
• On cell body (dendritic shafts, initial segment of axon)
 Inhibitory (10%)
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Classes of neurons
Based on:
A. Function
B. number of processes that originate from the cell
body
C. electrical activity
D. type of NT they synthesize and release
E. shape
F. location
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Classes of Neurons cont….
A. On the basis of function
a. Afferent Neurons (=Sensory Neurons)
i. Transmit information into the CNS from receptors.
ii. Mostly, have no dendrites.
iii. Cell body + long peripheral processes are outside the CNS.
• Only the short central process enters the CNS.
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b. Efferent Neurons (= Motor Neurons)
i. Transmit information out of the CNS to effectors (neurons,
muscles or glands).
ii. Cell body, dendrites and small segment of the axon, in CNS.
• Most of the axon is outside the CNS.

c. Interneurons
i. Function as integrators and signal changers.
ii. Integrate groups of afferent and efferent neurons into reflex
circuits.
iii. Lie entirely within CNS.
iv. Account for 99% of all neurons
(A: E: I, 1:10:200,000)
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B. On the basis of number of processes that originate
from the cell body
a. Unipolar Neurons
i. Have a single primary process
ii. Common in Invertebrate organisms.
iii. In vertebrate: Autonomic nervous system (Dorsal root
ganglia)
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b. Bipolar Neurons
i. Two processes (axon + dendrites))
• Dendrite: conveys information from the periphery of the
body.
• Axon: carries information toward the CNS.
ii. Many of sensory cells (retina, auditory, vestibular,
olfactory) are bipolar neuron.

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c. Multipolar Neurons
i. Predominate in the nervous system of vertebrates.
ii. Single axon and many dendrites.
Excitable cells, by H.F

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C. On the basis of electrical activity
a. Silent Neurons
• Steady unchanging RMP in the absence of external stimulation.
silent

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c. Bursting Neurons
• Fire spontaneously in the absence of external stimulation.
Significance:
• Generate rhythmic behaviors (breathing, …)
• Secrete neurohormones (OXT, AVP(arginine vasopressin))
Bursting

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D. On the basis of type of NT they synthesize and release
• Glutamatergic
• Cholinergic
• Adrenergic...
E. On the basis of their location
• Cortical neurons
• Spinal neurons
•... etc.

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Neuroglia (=Glial cells; Glia (Gk)→‘Nerve glue’)
• This is the specialized connective tissue of the NS.
i. Supportive matrix.
ii. 1013 glial cells (1:10)
iii. NOT directly involved in signal processing.
iv. accounts 40% of the total volume of CNS.(b/c of small in
size)

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Types of Neuroglia
I. Peripheral
 Schwann cells
 Satellite cells (ganglionic gliocytes),
II. Central
 Astrocytes
 Oligodendrocytes
 Microglia
 Ependymal cells
 Polydendrocytes

Synaptic transmission
Synapse
• A site at which an impulse is transmitted from one cell to another
• The second cell can be neuron or an effectors cell.
 There are 3 types of synapses
1. Neuroneuronal junction (presynaptic and postsynaptic
neurons)
2. Neuromuscular junction
3. Neuroglandualr junction
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Synaptic transmission… cont’d
 Synaptic transmission: Communication among neurons, with
muscles and glands.
• An average a neuron forms about 1000 (103) synaptic
connections.
• Human brain contains 1012 neurons (1012 x 103 = 1015
synaptic connections )
 Two types of synaptic transmission (chemical and electrical)
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A. chemical synapse
 Communication is achieved via neurotransmitters (glutamate,
Ach, serotonin, GABA, glysine,etc.)
 A chemical synapse is composed of:
i. Presynaptic Terminal:
 The first neuron that sending out information
 Contains NTs synthesizing enzymes, synaptic vesicle
transporters, reuptake transporters , active zone, Voltage-
gated Ca2+ channels …
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A. Chemical synapse… cont’d
ii. Synaptic cleft: the space b/n synapse.
 Width: 30nm (x = 20-50nm)
 Contains- Inactivating enzymatic system
iii. Postsynaptic terminal:
 A second cell or neuron that receive information
 Contains receptor for NT
• Transmitter-gated ion channels (ligand-gate ion channels
/Ionotropic receptors) or
• G protein-gated ion channels /Metabotropic receptors
Signal transmission through 2nd messenger cascades
(cAMP, cGMP, …)
67

Characteristics of Chemical Neurotransmission
a. Unidirectional/anterograde
b. Graded potential (amount of NT release  frequency of
stimulation)
c. Synaptic delay (0.5 -1.0ms)
d. Fatigue -↓in response of postsynaptic neurons after
repetitive stimulation by the presynaptic neurons
c. Transmitter inactivating enzymatic system in the synaptic
region
d. Net effect is the algebraic sum of the inhibitory and
excitatory effects
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Classification of Chemical synapse on functional basis
I. Excitatory synapse
 Cause for the generation of EPSP.
 Presynaptic neuron  neurotransmitter (Ach, glutamate,
serotonin ...)  open cation channels  influx of Na+ 
depolarization of the postsynaptic membrane towards the
threshold potential  EPSP.
• Neuron → action potential
• Muscle → contraction
• Glands → secretion
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II. Inhibitory synapse
 Cause for the generation of IPSP.
 Presynaptic neuron  neurotransmitters (GABA, glycine ...) 
open Cl- channels  Cl- enters into the cell  postsynaptic
membrane hyperpolarized  suppress firing in postsynaptic cell
 IPSP.

Sequence of events at chemical synapses
Action potential in presynaptic cell
↓
Depolarization of plasma membrane of the presynaptic axon
terminal
↓
Entry of Ca2+ into presynaptic terminal
↓
Release of the transmitter by the presynaptic terminal
↓
Chemical combination of the transmitter with specific receptors in
the plasma membrane of the postsynaptic cell
↓
Transient change in the conductance of the postsynaptic plasma
membrane to specific ions.
↓
Transient change in the Em of the postsynaptic cell 74

Effects of the Neurotransmitter
76
 Different neurons can contain different NTs.
 Different postsynaptic cells may contain different receptors.
 Thus, the effects of NT can vary.
 Some NTs cause cation channels to open, which results in a
graded depolarization.
 Some NTs cause anion channels to open, which results in a
graded hyperpolarization.

Neurotransmitter Removal
77
 Neurotransmitters are removed from the synaptic cleft via:
 Enzymatic degradation
 Diffusion
 Reuptake

B. Electrical synapses
 Two neurons can be coupled electrically to each other via gap
junctions.
 A gap junction is a protein pore complex (connexon) that lets
ions and other small molecules move between cells.
 Rapid electrical signaling and information (e.g. in reflex
reactions: escape and defensive responses)
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Characteristics of electrical synapses
a. A ΔEm in one cell is transmitted to the other cell by the direct
flow of current (cytoplasmic bridge/gap junction between
cells).
b. No synaptic delay (direct interactions between neighboring
cells).
c. Allow conduction in both directions(information flow is
bidirectional).

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Chemical Vs electrical synapses
Property Chemical synapse Electrical synapse
a. Distance between
presyn - postsyn 30-50nm 3-5nm
b. Cytoplasmic continuity No yes
c. Ultra-structural Presynaptic active zones
components vesicles, postsynaptic Gap junctions
receptor,…
d. Agent of transmission Chemical transmission Ionic current
e. Synaptic delay 0.5ms Virtually Ø
f. Direction of transmission Unidirectional Bidirectional

Synaptic Integration
• A central neuron receives both excitatory and inhibitory
signals.
• Excitatory and inhibitory signals are integrated into a single
response by the postsynaptic cell.
• Excitatory synaptic action is usually mediated by glutamate-
gated channels, that conduct Na+.
• Inhibitory synaptic action is usually mediated by GABA &
glycine-gated channels that conduct Cl-.
• Net effect is algebraic sum of excitatory + inhibitory signal
inputs.
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Synaptic Integration…
83
 One EPSP is usually not strong enough to cause an AP.
 However, EPSPs may be summed.
 There are two types of summation:
 Temporal and spatial
1.Temporal summation: This is when same presynaptic
neuron stimulates the postsynaptic neuron multiple times in a
brief period. EPSPs may be able to cause an AP
2. Spatial summation: Multiple presynaptic neurons all
stimulate a postsynaptic neuron resulting in a combination of
EPSPs which may yield an AP

• If excitatory signals > inhibitory signals → depolarization/excitatory
If inhibitory signals > excitatory signals → hyperpolarization/inhibitory.
85

• Action potential is initiated at the initial segment, axon
hillock.
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Fig . AP generation

Muscle Physiology
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Functions of Muscular System:
– Body movement
– Maintenance of posture
– Blood pumping
– propulsion of contents through various hollow
internal organs
– Emptying the contents of certain organs to the
external environment
– Control of body openings
– Heat production…..
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 General Points:
– Muscle cells can be excited chemically, electrically +
mechanically.
– 45-50% of the total body mass (≈ 600 muscles)
– 40% skeletal muscles + 10% cardiac and smooth muscles.
– 25% total bodily O2 consumption at rest is consumed by
the muscles.
– During strenuous exercise this amount can increase as
much as 10-20 times.
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Properties of Muscular Tissue
Contractility
• Ability of a muscle to shorten with force
Excitability
• Capacity of muscle to respond to a stimulus
Extensibility
• Muscle can be stretched
Elasticity
• Ability of muscle to recoil to original resting length
after stretched
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Types of muscle tissue
1. Skeletal Muscle
2. Cardiac Muscle
3. Smooth Muscle
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i. Skeletal Muscle
• Associated with & attached to the skeleton.
• Under our conscious (voluntary) control.
• Microscopically the tissue appears striated.
• Cells are long, cylindrical & multinucleate.
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ii. Cardiac muscle tissue:
– Makes up myocardium of heart
– Unconsciously (involuntarily) controlled
– Microscopically appears striated.
– Cells are short, branching & have a single nucleus.
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iii. Smooth muscle tissue:
– Makes up walls of organs & blood vessels
– Tissue is non-striated & involuntary
– Cells are short, spindle-shaped & have a single nucleus
– Tissue is extremely extensible, while still retaining
ability to contract.
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Categorization of muscle:
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1. Skeletal Muscle Physiology
• Make up about 40% of the body
• Linked to bones by bundles of tendons
• Composed of numerous muscle fibers
• A single skeletal muscle cell is called muscle fiber.
• Bundles of muscle fibers are called fascicles.
• Each muscle fiber contains many myofibrils which in turn are
composed of myofilaments.
• Myofilaments are composed of thick and thin filaments that give
rise to band(striations).
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Organization of skeletal muscle
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Skeletal Muscle Fiber
• Sarcolemma:
• Muscle cell plasma membrane
• Sarcoplasm:
– The spaces b/n the myoﬁbrils are ﬁlled with ICF
called sarcoplasm.
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 Sarcoplasmic Reticulum (SR):
– Tubular sacs similar to smooth ER.
– Parallel to the myofibrils
– Stores Ca2+
– Action potential releases Ca2+ from the vesicles
– Release of Ca2+ triggers muscle contraction
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Transverse Tubules:
• Closely associated with SR.
• Connected to the sarcolemma.
• Penetrate the sarcolemma into the interior of the muscle cell
(invaginations).
• Bring extracellular materials into close proximity of the deeper
parts of the muscle fiber.
• Transmit nerve impulses from the sarcolemma to the myofibrils.
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Myofibrils.
• Cylindrical intracellular structures that extend the entire
length of the muscle fiber.
• Each myofibril consists of a regular arrangement of
highly organized cytoskeletal elements—the thick and
the thin filaments.
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Components of myofibril
• A myofibril displays alternating dark bands (the A bands)
and light bands (the I bands).
• The bands of all the myofibrils lined up parallel to one
another collectively produce the striated or striped
appearance.
• Alternate stacked sets of thick and thin filaments that
slightly overlap one another are responsible for the A and I
bands.
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A- band
• Dark area where actin and myosin overlap
• Equal to the length of the thick Myofilaments
(myosin).
H band
Light area at center of A band
It contains only myosin tails
There are no thin filaments.
visible when the muscle is relaxed
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M-lines:
a. Site of the reversal polarity of the myosin molecules in
each of the thick filaments.
b. It vertically bisects the H-Band
c. It contains 2 important proteins:
– Myomesin: a structural protein that links neighboring
thick filaments.
– Creatinine Phosphokinase: an enzyme that maintains
adequate ATP conc. in working muscle fibers.
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I-band
– Consists of the remaining portion of the thin filaments that do not
project into the A band.
– Visible in the middle of each I band is a dense, vertical Z line.
– The area between two Z lines is called a Sarcomere.
Z-lines = borders of the sarcomere
– Perpendicular to long axis of the muscle fiber
– is a flat, cytoskeletal disc that connects the thin filaments of two
adjoining sarcomeres.
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Sarcomere:
• Is the functional unit of skeletal muscle.
• The Sarcomere is the smallest portion of skeletal muscle
capable of contracting.
• Is the distance between two Z-lines
• About 10,000 sarcomeres per myofibril, end to end
• The resting length of a sarcomere is 2µm-2.2µm.
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• Sarcomere cont…
• It consists of three types of proteins:
1. Contractile proteins
2. Regulatory proteins
3. Structural proteins
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Thin Myofilaments:
• Composed of 3 major proteins
– Actin
– Tropomyosin
– Troponin
Actin:
• The primary structural proteins of the thin filament.
• Contractile protein!!
• Each actin molecule has a special binding site for attachment
with a myosin cross bridge.
• Binding of myosin and actin molecules at the cross bridges
results in contraction of the muscle fiber.
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Regulatory Proteins:
1. Tropomyosin:
– An elongated protein winds along the groove of the actin
double helix.
– Blocks the myosin binding sites on the G-actin molecules.
2. Troponin: is composed of three subunits:
– Tn-I : Binds with actin and inhibits the interaction of myosin
with actin.
– Tn-T: binds to tropomyosin,
– Tn-C: binds to calcium ions.
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The structural relationship between troponin, tropomyosin, and actin. The
tropomyosin is attached to actin, whereas the troponin complex of three
subunits is attached to tropomyosin (not directly to actin)
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Myosin (Thick) Myofilament:
• Composed of a rod-like tail and two globular heads.
• The tails form the central portion of the myosin
myofilaments.
• The two globular heads face outward and in opposite
directions.
• Interact with actin during contraction.
• Has 2 heads → Myosin head (cross-bridge) → Actin-
binding site.
→ ATP-binding site (ATPase) → Hydrolyzes ATP.
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Titin:
• Structural protein.
• Stabilize the position of the thick filaments in relation to
the thin filaments;
• Connects myosin to the Z-lines in the sarcomere
• It is very elastic.
• Able to stretch up to 3 times its resting length.
• Is responsible for muscle flexibility.
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Process of Muscle Contraction
Innervations of the Skeletal Muscle:
• A skeletal muscle is supplied by a group of motor nerve fibers
that originate from large motor neurons in the spinal cord.
• After entering the muscle, each motor nerve fiber divides in to
several branches.
• Each branch of the nerve fiber innervates one muscle fiber.
• The junction between the nerve fiber and the muscle fiber is
called the neuromuscular junction.
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Motor Unit
• A motor unit is a motor neuron and all the muscle fibers
it supplies.
• The number of muscle fibers per motor unit can vary
from a few (4-6) to hundreds (1200-1500).
• Muscles that control fine movements (fingers, eyes)
have small motor units.
• Large weight-bearing muscles (thighs, hips) have large
motor units.
7/28/2022 123

Neuromuscular Junction:
 It is the site where motor neuron stimulates(meets) a
muscle cell (fiber).
• Axon terminal
o The swollen distal end of axon ,contains neurotransmitters within
the synaptic vesicle.
• Synaptic cleft
o The space between the axon terminal and the folded region of the
muscle cell membrane.
• Motor end plate
o The folded portion of the sarcolemma in close contact with the
synaptic ending of the axon terminal.
7/28/2022 126

• The axon terminal releases a neurotransmitter from the
motor neuron into the synaptic cleft.
• The neurotransmitter is acetylcholine (ACh).
• This neurotransmitter is synthesized by the nerve cell
and stored in synaptic vesicles.
• When a nerve impulse reaches the axon terminal, the
synaptic vesicles release acetylcholine into the
synaptic cleft.
7/28/2022 127

• Acetylcholine rapidly diffuses across the synaptic cleft to
combine with receptors on muscle cell membrane.
• ACh causes ligand gated sodium channels to open and
depolarization of the muscle cell membrane.
• Acetylcholine bound to the receptor is rapidly
decomposed by acetylcholinesterase preventing
continuous stimulation of the muscle fiber.
7/28/2022 128

Excitation-Contraction Coupling:
• Sequence of events that links the nerve impulse and skeletal muscle
contraction.
• Is the process of linking ∆Em/AP to muscle contraction.
 Electrical events precedes mechanical events (2ms, 100ms).
• Motor Neurons – stimulates skeletal muscle contraction.
• When a skeletal muscle cell receives input from a motor neuron, it
depolarizes.
• Depolarization causes the muscle cell to fire an action potential.
7/28/2022 130

Remember!!!
Dihydropyridine (DHP)
• DHP is a voltage-gated Ca2+ channel located in the
sarcolemmal membrane
• Although it is a voltage-gated Ca2+ channel, Ca2+ does not
flux through this receptor in skeletal muscle. Rather, DHP
functions as a voltage-sensor.
• When skeletal muscle is at rest, DHP blocks RyR
Ryanodine Receptor (RyR)
• RyR is a calcium channel on the SR membrane.
• When the muscle is in the resting state, RyR is blocked by DHP
• Thus, Ca2+ is prevented from diffusing into the cytosol.
7/28/2022 131

Stimulation of Contraction
an action potential in the transverse
tubule that causes a conformational
change in the voltage-sensing
dihydropyridine (DHP) receptors,
opening the Ca++ release channels in
the sarcoplasmic reticulum and
permitting Ca++ to rapidly diffuse into
the sarcoplasm and initiate muscle
contraction.
7/28/2022 132

Then what happens….?
• The rise in cytosolic Ca2+ opens more RyR channels (calcium-
induced calcium release)
• Calcium ions bind to troponin- C causing a conformational
change of tropomyosin.
- Troponin pushes tropomyosin away thus exposing the active
site that it is covering on actin.
• Myosin binds to the exposed active site of actin.
• Myosin crossbridges pull the actin myofilament toward the
center of the sarcomere.
7/28/2022 133

• Each myosin cross bridge must attach and reattach many times
during a single contraction
“Called crossbridge cycling”
• Attachment of the myosin cross bridge to actin requires energy.
• Breakdown of ATP into ADP and P provides the energy required
for pulling on the actin myofilament
• ATP-ase catalyzes the breakdown of ATP
• Myosin then remains bound to actin until it binds to another
ATP.
• The cycle of attachment, and release continues as long as
calcium and ATP remain available.
7/28/2022 135

The Sliding-Filament Model:
(The actin filaments slide over myosin filaments)
• When a muscle
contracts it
decreases in length
as a result of the
shortening of its
individual fibers.
• Shortening of the
muscle fibers, in
turn, is produced by
shortening of their
myofibrils, which
occurs as a result of
the shortening of
the distance from Z
disc to Z disc
7/28/2022 136

Resting state
i. Interaction of thick and thin filaments is inhibited.
ii. Troponin I & tropomyosin covers the sites where myosin heads bind to actin
Activated States:
Influx of Ca2+
↓
Binds to Troponin C (Ca2+)
↓
Conformational change in troponin
↓
Tropomyosin moves aside
↓
Exposes the myosin-binding sites on actin
↓
Myosin cross-bridge on the thick filament is exposed to actin filaments
7/28/2022 138

Why ATP is needed?
 For energizing the myosin cross-bridges.
 For dissociation of actin-myosin complex and
initiation of relaxation.
 To pump out Ca2+ from the sacroplasm to sequester it
into the SR (Ca2+ - pump).
7/28/2022 139

Structural changes during contraction:
Banding
– H-zone: Disappears
– I-band: Narrower/smaller
– A-band: Constant
Contractile proteins: No change in length of
myosin or actin
Sarcomere: Shortens
7/28/2022 141

Relaxation of Muscle:
a. Breakdown of Ach by Acetylcholinsterase.
b. Removal of Ca2+ from the cytosol into the SR for storage by Ca2+ -
ATPase
Then, after removal of Ca2+ :
I. Troponin returns to its original conformational state
II. Tropomyosin inhibition of myosin-Actin interaction is restored.
III. Cross-bridge cycling stops and the muscle is returned to its resting
state.
7/28/2022 143

Key Points
• Contraction-relaxation states are determined by cytosolic levels of
Ca2+
• The source of the calcium that binds to the troponin-C in skeletal
muscle is solely from the cell’s sarcoplasmic reticulum. Thus, no
extracellular Ca2+ is involved.
Two ATPases are involved in contraction:
• Myosin ATPase supplies the energy for the mechanical aspects of
contraction by putting myosin in a high energy and affinity state.
• SERCA pumps Ca2+ back into the SR to terminate the contraction, i.e.,
causes relaxation.
7/28/2022 145

Muscle Mechanics
• Muscle tension
• The pulling force on the tendons
• Muscle cells generate tension when contracting.
• Muscle twitch
• A brief contraction-relaxation
• Is the response of the muscle fibers to a single action
potential.
 Tetany
• Sustained contraction of a muscle
• Result of a rapid succession of nerve impulses
7/28/2022 146

Types of Muscle Contraction
i. Isometric:
– No change in length but tension increases
– Used in standing, sitting and maintaining our
posture.
ii. Isotonic:
– Change in length but tension constant
– Used in walking, moving any part of the body
7/28/2022 147

Energetics of Muscle Contraction
I. Available ATP:
– There is a limited supply of readily available ATP
– A small amount of ATP is stored in the myosin
Crossbridges immediately available when the muscle
begins to contract.
– Contraction uses up this source of ATP in about 6
seconds making it necessary to have other sources of
ATP available.
7/28/2022 148

II. Creatine Phosphate (CP):
– When the stored ATP in the myosin crossbridges
are exhausted, ADP and CP are used to regenerate
ATP.
• CP + ADP = ATP + Creatine.
– The energy available from stored ATP and from the
reaction of joining ADP with CP provides only about
20 seconds worth of energy .
7/28/2022 149

III. Glucose:
– Cellular respiration of glucose is an energy source
utilized to generate ATP
– Muscle contractions that are longer than 15 - 20
seconds depend on cellular respiration of glucose as
a source of ATP.
– The majority of the ATP used by muscles is formed
by aerobic processes in the mitochondria.
7/28/2022 150

Functional characteristics of skeletal muscle fiber:
• Skeletal muscle fibers can be
divided on the basis of their
contraction speed (time required
to reach maximum tension)
• a= Fast-Glycolytic Fibers
(Type IIb)
• b= Fast-Oxidative-Glycolytic
Fibers (Type IIa)
• c= Slow-Oxidative Fibers
(Type I)
7/28/2022 151

Characteristics of the Three Types of Skeletal
Muscle Fibers
7/28/2022 152

Notice
Slow twitch oxidative fibers (red muscle):
 Muscles of the back and neck (gross sustained mov’t.)
Type IIB: Fast glycolytic fibers (white muscles):
 Muscles of the hand, extraocular muscles (fine, rapid,
precise mov’t.)
7/28/2022 153

Oxygen Debt
• When exercise stops, the body's need for oxygen continues
for a period of time.
• The body responds to this need by continuing to breathing
heavily until all the sources of ATP have been replenished.
• The amount of oxygen necessary to restore the resting
metabolic state of the body is called oxygen
debt/recovery oxygen consumption.
7/28/2022 154

 Oxygen debt includes the oxygen needed to:
• Restore muscles to their resting metabolic condition
• Convert lactic acid to pyruvic acid in the liver
• Replenish cellular stores of glycogen, creatine
phosphate, and ATP
7/28/2022 155

Muscle fatigue:
• Occurs when an exercising muscle can no longer
respond to stimulation with the same degree of
contractile activity.
Causes:
Accumulation of lactate
Depletion of glycogen energy reserves
Central fatigue:
• occurs when the CNS no longer adequately activates the
motor neurons supplying the working muscles.
7/28/2022 156

Muscle hypertrophy
• An increase in the actual size of the muscles
• can be increased by regular bouts of anaerobic, short-duration,
high-intensity resistance training, such as weight lifting.
• An increase in diameter of the fast-glycolytic fibers.
• Most of the fiber thickening results from increased synthesis of
myosin and actin filaments.
Muscle hyperplasia ???: an increase in fiber number
7/28/2022 157

• Muscle Atrophy:
• If a muscle is not used, its actin and myosin content
decreases.
• Muscle decreases in mass and becomes weaker.
i. Disuse atrophy:
- occurs when a muscle is not used for a long period
of time even though the nerve supply is intact.
ii. Denervation atrophy: occurs after the nerve supply
to a muscle is lost.
7/28/2022 158

Clinical Correlates
Rigor Mortis
• It is a state of muscle contracture, i.e., contraction
produced not followed by relaxation.
• It is a contracture which occurs in the muscles after
death.
• The rigidity is due to depletion of ATP from the muscle.
Which is required to cause separation of the cross-bridges
from the actin filaments during the relaxation process
7/28/2022 159

Myasthenia Gravis:
• Is an autoimmune disease in which acetylcholine receptors
at the postsynaptic neuromuscular junction are destroyed by
antibodies.
• It causes muscle paralysis.
• The end plate potentials that occur in the muscle fibers are
too weak to initiate opening of the ligand-gated sodium
channels
• If the disease is intense enough, the patient dies of paralysis
in the respiratory muscles.
160

Lambert-Easton syndrome
• Lambert-Easton is also an autoimmune condition, but
the antibodies block the presynaptic voltage-gated
Ca2+ channels.
7/28/2022 161

Botulinum toxin
• bacterial poison
• is a protease that destroys proteins needed for
the fusion and release of synaptic vesicles.
• toxin targets cholinergic neurons, resulting in
skeletal muscle paralysis
7/28/2022 163

Latrotoxin
• venom from the black widow spider,
• opens presynaptic Ca2+ channels, resulting in
excess Ach release.
7/28/2022 164

Cardiac Muscle
• It has SAME contractile machinery as skeletal muscle with some
degree of modification.
o Has a single nucleus which is smaller
o A cardiac cells are joined end-to-end by intercalated discs
o Contain gap junctions which is synchronizing the contractions of
heart muscle cells.
 REGULATION
Neuronal (ANS) + hormonal
165

Excitation-Contraction coupling in cardiac muscle
calcium dependent calcium release
 T-Tubule (DHPR) contains Ca2+ channel (through which Ca2+
enters the cell during the AP).
 SR-RyR containing Ca2+ - release channel is opened by influx of
Ca2+ from the T-Tubule.
• The rise in cytosolic Ca2+ opens more RyR channels (calcium-
induced calcium release)
• Ca2+ binds to troponin-C, which in turn initiates cross-bridge
cycle, creating active tension.
7/28/2022 166

COMPARISON OF STRIATED MUSCLES
(SKELETAL VS. CARDIAC)
Similarities
• Both have the same functional proteins, i.e., actin,
tropomyosin, troponin, myosin, and titin.
• A rise in cytosolic Ca2+ initiates cross-bridge cycling
thereby producing active tension.
• ATP plays the same role.
• Both have SERCA.
• Both have RyR receptors on the SR and thus show calcium-
induced calcium release.
7/28/2022 169

Differences
• Extracellular Ca2+ is involved in cardiac contractions, but
not skeletal muscle. This extracellular Ca2+ causes
calcium-induced calcium release in cardiac cells.
• Cardiac cells are electrically coupled by gap junctions,
which do not exist in skeletal muscle.
• Cardiacmyocytes remove cytosolic Ca2+ by 2 mechanisms:
SERCA and a Na+—Ca2+ exchanger (3 Na+ in, 1 Ca2+
out) on the sarcolemmal membrane. Skeletal muscle only
utilizes SERCA.
7/28/2022 170

Differences cont…
Cardiac cells have a prolonged
action potential. (muscle starting
to relax) while the action potential
is still in the absolute refractory
period.. This has approximately
equal mechanical and electrical
event prevents summation of the
force and if the muscle can’t
summate, it can’t tetanize.
7/28/2022 171

• But in skeletal muscle,
because the membrane has
repolarized well before force
development, multiple action
potentials can be generated
prior to force development.
• This summation can continue
until the muscle tetanizes in
which case there is sufficient
free Ca2+ so that cross-bridge
cycling is continuous.
7/28/2022 172
Differences cont…

Smooth Muscle
• It is important in regulation of the airways, blood
vessels, GIT, and hollow organs (bladder, uterus...)
• It is controlled by intrinsic factors (inherent
rhythmicity): ANS + HORMONES.
7/28/2022 173

• It has NO STRIATIONS (sparse thick filaments).
• Sarcomeres are absent.
• Thick filaments: myosin
• Thin filaments: actin and tropomyosin (No troponin)
instead, has calmodulin
• Thick and thin filaments are dispersed through out the
cell.
7/28/2022 174

Types of Smooth muscle:
1. Single unit smooth muscle (Visceral smooth muscle)
 Are large sheets of mononucleated small cells.
 Have low resistance bridge of gap junctions.
 Show synchronous excitation and contractions. (=
functional syncytium)
 Have unstable RMP (resting membrane potential.)
 Found in gut, ureter, blood vessels and uterus.
.
7/28/2022 176

2. Multiunit smooth muscles
• Multi-unit smooth muscle is composed of discrete,
separate smooth muscle fibers.
• Each fiber operates independently of the others and
often is innervated by a single nerve ending, as
occurs for skeletal muscle fibers (ANS)
 Ciliary muscle of the eye, the iris of the eye, and the
piloerector muscles
7/28/2022 177

Smooth muscle cell contraction:
• A key difference here is that cross-bridge activity in
smooth muscle is turned on by calcium-mediated changes
in the thick filaments, whereas in striated muscle, calcium
mediates changes in the thin filaments.
• Regulation of contraction is thus myosin based in
smooth muscle, rather than actin based as it is in
skeletal and cardiac muscle
7/28/2022 178

Steps of smooth muscle contraction
1. The calcium ions bind with calmodulin; the calmodulin-calcium
complex then join with and activates myosin kinase, a
phosphorylating enzyme.
2. One of the light chains of each myosin head, called the regulatory
chain, becomes phosphorylated in response to the myosin kinase.
3. When the regulatory chain is phosphorylated, the head has the
capability of binding with the actin filament, causing muscle
contraction. When this myosin light chain is not phosphorylated, the
attachment–detachment cycling of the head with the actin filament
does not occur.
7/28/2022 179

Don’t forget!!!!
• Most of the calcium ions that cause smooth muscle
contraction are from ECF that enter at the time of the
action potential or other stimulus.
• Calcium released from SR is very minimal so that it
has no paramount effect.
NB:
skeletal muscle= virtually all from SR
cardiac muscle= both ECF and SR calcium
7/28/2022 183

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