Vesicular transport of peptide hormones and neurotransmitters:

• Some of the hormones and

neurotransmitters
(neuropeptides) are
peptides.
• The synthesis begins with
transcription process in the
nucleus.
• Nucleus (transcription) →
ribosomes (translation) →
GER → Golgi
• Peptides are packaged into
the transport vesicles
(secretory vesicles) in the
Golgi.
Vesicular transport of peptide hormones and neurotransmitters:

• In neurons, secretory vesicles are

transported along the axon to the
presynaptic axon terminal.
• Secretory vesicles dock to the
presynaptic membrane.
• They are stored at the axon
terminal.
• Secretory vesicles do not
immediately fuse with the cell
membrane.
• Instead, they pause for a while at
this point until the neuron is
stimulated and an action potential
is triggered.
• Peptide and amine hormones are
released from the endocrine glands
using a similar secretory pathway.
Exocytosis of classical neurotransmitters (eg. acetylcholine, noradrenaline,
dopamine, glycine, GABA, serotonin, glutamate):
• Classical neurotransmitters are not peptides!
• They are synthesized in the cytoplasm at the axon terminal.
• Then, they are transported into the transport vesicles budding from presynaptic
membrane: synaptic vesicle formation!
• Synaptic vesicles approach and dock to the presynaptic membrane.
• However, they pause at this point and they are stored.
• In order to trigger the fusion of secretory or synaptic vesicles, the neuron or
the endocrine cell must be stimulated!
• The stimulus in an endocrine cell is a small depolarization of the cell
membrane.
• The stimulus in a neuron is the action potential of the membrane.
In neurons:
• Action potential spreads along the axon and causes the release of
neurotransmitters to the synaptic cleft.
RESTING MEMBRANE POTENTIAL
• Two electrodes:
Reference electrode
Recording electrode

• When two electrodes are placed

outside the neuron, there is zero
potential difference across the
membrane.

However,
• When the recording electrode is
placed inside the axon, a
negative membrane potential is
recorded.
• Cell membrane is polarized
during resting conditions.
• Principle of electroneutrality of body compartments: In the first figure,
intracellular and extracellular compartments are electrically neutral.

• However, in reality, there is a slight excess of negative ions (anions) inside

the cells and a slight excess of positive ions (cations) outside the cells.
• Coulomb force (electrostatic force): opposite charges attract each other!

• The excess anions inside the cell attract the excess cations outside the cell.
• Ions move toward the cell membranes.
• However, cell membranes are impermeable to ions.
• Therefore, anions and cations line up along each side of the membrane creating
a negative resting membrane potential.
• Polarized Cell = cells with resting membrane potential.

• Negative resting membrane potential exists across the cell membrane

of all body cells: -5 mV → -100 mV

• Resting Membrane Potential: In neurons: -60 mV - -70 mV

Formation of Resting Membrane Potential in Neurons
1. Na+/K+ ATPase pump: It has two contributions to the resting membrane
potential:
• It pumps 3 Na+ ions out of the cell for every 2 K+ ions pumped in. This
action increases the negativity inside the cell!

• It establishes the concentration gradients for K+ (high inside, low outside)

and Na+ (low inside, high outside).

2. K+-leak channels: They are continually open!

• At rest, voltage-gated ion channels are closed, whereas K+-leak channels
are open.

• Therefore, cell membrane is permeable mainly to K+ at rest!

• K+ diffuses down its concentration gradient and leaves the cell causing a
net buildup of negative charges inside the cell.
Ionic Composition of Extracellular and Intracellular Compartments

Extra. Concen. (mM) Intra. Concen. (mM)

Na+ 145 15
K+ 4 150
Ca2+ 10-3 M 10-7 M
Mg2+ 1.5 12
Cl- 110 10
HCO3- 24 10
Pi 2 40
Amino acids 2 8
Glucose 5.6 1
ATP 0 4
Protein 0.2 4
 ELECTRICALLY EXCITABLE CELLS

• Neurons, muscle cells and some endocrine cells share a common property
which distinguishes them from other cells.

• These cells are capable of changing their membrane potentials when they are
stimulated.

• Stimuli → neuron, muscle cell, endocrine cell → (-) resting membrane

potential shifts to more positive potentials (depolarization or action potential)

• In neurons→ action potential → exocytosis of neurotransmitters → synaptic

transmission
• In muscle cells → action potential → contraction → body movement
• In endocrine cells → depolarization → exocytosis of peptide or amine
hormones
 ACTION POTENTIAL

• When a stimulus with a strength adequate to decrease the membrane

potential to -55 mV is applied to an axon, threshold of action potential is
reached.
• Action potential involves two main phases in neurons:
1. Depolarization phase: When threshold is reached, voltage-gated Na+ channels
open → Na+ diffuses down its concentration gradient and into the cell →
membrane is depolarized to +35 mV.
2. Repolarization phase: When membrane potential reaches +35 mV, voltage-
gated Na+ channels inactivate and voltage-gated K+ channels open → Na+
influx ceases and K+ diffuses down its concentration gradient and out of the
cell → membrane potential returns back to its resting values.
ALL OR NONE LAW • When the magnitude (strength) of a
stimulus is increased from a
minimum value to a maximum, no
action potentials are obtained with
weak stimuli.

• However, when the threshold (-55

mV) is reached, the first action
potential is triggered.

• If we keep on increasing the

stimulus strength, each stimulus
will be followed by an action
potential.

• However, the size (or amplitude) of

the action potential will always be
the same!
In a neuron:

• Voltage-gated ion channels are localized mainly in the axonal membrane.

• Therefore, action potential develops mainly on the axonal membrane.

LOCALIZATION OF VOLTAGE-GATED ION CHANNELS
ON THE AXONAL MEMBRANE
 UNMYELINATED AXONS

• Some axons are unmyelinated.

• Voltage-gated Na+ and K+ channels are distributed

homogeneously/uniformly along the unmyelinated axon.
PROPAGATION OF ACTION POTENTIAL ALONG THE UNMYELINATED AXONS

• Action potential, first, opens the voltage-gated Na+ channels at the initial
segment.
• Entrance of the Na+ ions triggers a K+ flow inside the axon creating a
depolarization wave.
• When spreading from the initial segment to the axon terminal, depolarization
wave opens each voltage-gated Na+ channel it encounters on the axon
membrane : continuous conduction
• Continuous conduction is SLOW!
 MYELIN SHEATH

• Some axons are myelinated.

• Glial cells wrap around the axon to form the myelin sheath.
• Initial segment and the nodes of Ranvier are not covered with myelin
sheath.
• Action potential starts at the initial segment of the axon.
• Voltage-gated Na+ channels are located only at the initial segment and at
the nodes of Ranvier.
PROPOGATION OF ACTION POTENTIAL ALONG MYELINATED AXONS

• Action potential begins at the initial segment: opens the voltage-gated Na+
channels.
• Entrance of the Na+ ions triggers a K+ flow inside the axon.
• K+ flow spreads down the axon and opens the voltage-gated Na+ channels
gathered only at the nodes of Ranvier.
• Action potential propagation is slow at nodes of Ranvier.
• Action potential propagation is fast beneath the myelinated segments called
the internodal segments.
PROPOGATION OF ACTION POTENTIAL ALONG MYELINATED AXONS

• The fast propogation of action potential under myelinated segments and the
slow propogation at the nodes of Ranvier along the myelinated axons is called
saltatory conduction: fast, slow, fast, slow, …..

• The speed of conduction is much higher in myelinated axons when compared

to unmyelinated axons.
 SYNAPTIC TRANSMISSION

Components of a synapse:
1.Presynaptic axon terminal

2.Synaptic cleft

3.Dendrite or soma of the postsynaptic neuron

 SYNAPTIC TRANSMISSION

• There are synaptic vesicles in the axon terminal.

• Neurotransmitters are stored in these vesicles.

• Synaptic vesicles dock at the presynaptic membrane and wait until an

action potential arrives at the axon terminal.
 SYNAPTIC TRANSMISSION

1. An action potential spreads along the axon.

2. When the action potential arrives at the axon terminal, the depolarization
wave opens the voltage-gated Ca+2 channels located in the presynaptic
membrane.
3. Ca+2 diffuses down its concentration gradient and into the axon terminal.
 SYNAPTIC TRANSMISSION

3. Ca2+ diffuses into the cell and activates a special protein which enables the
fusion of synaptic vesicle membrane and cell membrane.
4. Neurotransmitters are released into the synaptic cleft: exocytosis!
5. Neurotransmitters cross the synaptic cleft by diffusion and bind to the specific
receptors expressed on the postsynaptic membrane on the dendrite or soma of
the postsynaptic neuron.
 SYNAPTIC TRANSMISSION

5. Some neurotransmitter receptors (ionotropic receptors) are ion channels

(ligand-gated ion channels).

• Binding of neurotransmitter to the ionotropic receptor directly opens the

channel.
 SYNAPTIC TRANSMISSION

6. Sometimes the neurotransmitter receptor is not an ion channel. However

when activated, these postsynaptic receptors trigger intracellular signaling
pathways inside the postsynaptic neuron.
• These signaling pathways indirectly open or close other ligand-gated
channels in the postsynaptic membrane.
 SYNAPTIC TRANSMISSION

• When a signaling pathway opens a ligand-gated channel, ion influx/efflux

occurs.

• When a signaling pathway closes a channel, ion influx/efflux stops.

• These changes lead to the formation of synaptic potentials on the

postsynaptic membrane!
When the positivity increases inside the cell (depolarization), excitatory
postsynaptic potential (EPSP) occurs. Causes of EPSP:

• Openning of ligand-gated channels permeable to Na+.

• Openning of ligand-gated channels permeable to Ca+2.

• Closing of ligand-gated channels permeable to K+.

When the negativity increases inside the cell (hyperpolarization),
inhibitory postsynaptic potential (IPSP) occurs. Causes of IPSP:

• Openning of ligand-gated channels permeable to Cl-.

• Openning of ligand-gated channels permeable to K+.

• Closing of ligand-gated channels permeable to Na+.

• Closing of ligand-gated channels permeable to Ca+2.

PROPERTIES OF SYNAPTIC POTENTIALS
• The amplitude of synaptic potentials are smaller than action potential.
• If positivity is increased inside the cell membrane (depolarization) → it is called
excitatory postsynaptic potential (EPSP)

• If negativity is increased inside the cell membrane (hyperpolarization) → it is

called inhibitory postsynaptic potential (IPSP)

• Ligand-gated ion channels lead to the formation of EPSPs or IPSPs.

 SIGNAL TRANSDUCTION ALONG THE NEURON

• Ligand-gated ion channels are localized mainly in the dendritic and soma
membrane.

Therefore,
• Synaptic potentials develop mainly on the dendritic and soma membrane.
 SYNAPTIC TRANSMISSION

• EPSPs and IPSPs are integrated on the postsynaptic neuron soma.

• If the sum of all EPSPs and IPSPs results in a depolarization which is sufficient to
reach the threshold (-55 mV), an action potential is triggered on the initial
segment of the axon.
 SYNAPTIC TRANSMISSION

• If the sum of all EPSPs and IPSPs results in a hyperpolarization on the

postsynaptic neuron soma, membrane potential moves away from the
threshold and action potential formation is inhibited.
• As a result, exocytosis of the neurotransmitters is suppressed. Synaptic
transmission is blocked.