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Nervous System
It is a system of the body which recieves information, integrates the received information and transmits
impulses to control different body functions in order to maintain homeostasis. The nervous system is divided into
the central nervous system (CNS), which includes the brain and spinal cord, and the peripheral nervous system
(PNS), which includes the cranial nerves arising from the brain and the spinal nerves arising from the spinal cord.
The nervous system is composed of only two principal types of cells called neurons and supporting cells.
Neurons

Neurons are the basic structural and functional units of the nervous system.

They are specialized to respond to physical and chemical stimuli, conduct electrochemical impulses, and
release chemical regulators. Through these activities, neurons enable the perception of sensory stimuli,
learning, memory, and the control of muscles and glands.

Most neurons cannot divide by mitosis, although many can regenerate a severed portion or sprout small
new branches under certain conditions.
Structure
Neurons have three principal regions: (1) Cell body, (2) Dendrites, and (3) Axon.

Cell body is the enlarged portion of the neuron that contains the nucleus. It is the “nutritional center” of
the neuron where macromolecules are produced. The cell body also contains densely staining areas of
rough endoplasmic reticulum known as Nissl bodies that are not found in the dendrites or axon. The cell
bodies within the CNS are frequently clustered into groups called nuclei (not to be confused with the
nucleus of a cell). Cell bodies in the PNS usually occur in clusters called ganglia (table 7.1).

Dendrites (dendron = tree branch) are thin, branched processes that extend from the cytoplasm of the
cell body. Dendrites provide a receptive area that transmits electrical impulses to the cell body.

Axon is a longer process that conducts impulses away from the cell body. Axons vary in length from only a
millimeter long to up to a meter or more (for those that extend from the CNS to the foot). The origin of the
axon near the cell body is an expanded region called the axon hillock; it is here that nerve impulses
originate. Side branches called axon collaterals may extend from the axon.
Classification of Neurons
Neurons may be classified according to their function or structure.
Functional classification The functional classification is based on the direction in which they conduct impulses.

Sensory, or afferent, neurons conduct impulses from sensory receptors to CNS.

Association neurons, or interneurons, are located entirely within the CNS, link the senory and motor
neurons and are involved in integrative, functions of the nervous system.

Motor, or efferent, neurons conduct impulses from CNS to effector organs (muscles and glands). There are
two types of motor neurons: somatic and autonomic.
 Somatic motor neurons are responsible for both reflex and voluntary control of skeletal muscles.
 Autonomic motor neurons innervate (send axons to) the involuntary effectors i-e., smooth muscle,
cardiac muscle, and glands.
Structural classification The structural classification of neurons is based on the number of processes that
extend from the cell body of the neuron.

Pseudounipolar neurons have a single short process that branches like a T to form a pair of longer
processes. Sensory neurons are pseudounipolar—one of the branched processes receives sensory stimuli
and produces nerve impulses; the other delivers these impulses to synapses within the brain or spinal cord.
The part of the process that conducts impulses toward the cell body can be considered a dendrite, and the
part that conducts impulses away from the cell body can be considered an axon.

Bipolar neurons have two processes, one at either end; this type is found in the retina of the eye.

Multipolar neurons, the most common type, have several dendrites and one axon extending from the cell
body; motor neurons are good examples of this type.
Supporting cells

Supporting cells aid the functions of neurons and are about five times more abundant than neurons.

In the CNS, supporting cells are collectively called neuroglia, or simply glial cells (glia = glue).

Unlike neurons, which do not divide mitotically, glial cells are able to divide by mitosis. This helps to explain
why brain tumors in adults are usually composed of glial cells rather than of neurons.

There are two types of supporting cells in the peripheral nervous system:
1. Schwann cells, which form myelin sheaths around peripheral axons; and
2. Satellite cells, or ganglionic gliocytes, which support neuron cells bodies within the ganglia of the PNS.

There are four types of supporting cells, called neuroglial (or glial) cells, in the central nervous system:
1. Oligodendrocytes, which form myelin sheaths around axons of the CNS;
2. Microglia, which migrate through the CNS and phagocytose foreign and degenerated material;
3. Astrocytes, which help to regulate the external environment of neurons in the CNS; cover capillaries of
the CNS and induce blood brain barrier.
4. Ependymal cells, which line the ventricles (cavities) of the brain and the central canal of the spinal cord.
Recent evidence suggests a more exciting role for the ependymal cells that line the ventricles of the brain,
and also for the astrocytes immediately adjacent to this region—they can function as neural stem cells.
That is, they can divide and their progeny can differentiate (specialize) along different lines, to become
new neurons and neuroglial cells. Reptile and bird brains have been known to generate new neurons
throughout life, but only recently has this ability been demonstrated in mammalian (including human)
brains.
Functions of Astrocytes

Astrocytes (aster=star) have numerous cytoplasmic extensions that radiate outward surrounding almost
entire surface of capillaries of the CNS as well as adjacent to the synapses. The astrocytes are thus ideally
situated to influence the interactions between neurons and between neurons and the blood.

Here are some of the proposed functions of astrocytes:
1. Astrocytes take up K+ from the extracellular fluid. Since K+ diffuses out of neurons during production of
nerve impulses, this function may be important in maintaining the proper ionic environment for neurons.
2. Astrocytes take up some neurotransmitters released from the axon terminals of neurons. For example,
the neurotransmitter glutamate is taken into astrocytes and transformed into glutamine. The glutamine is
then released back to the neurons, which can use it to reform the neurotransmitter glutamate.
3. The astrocyte end-feet surrounding blood capillaries take up glucose from the blood. The glucose is
metabolized into lactic acid, or lactate. The lactate is then released and use as an energy source by
neurons, which metabolize it aerobically into CO2 and H2O for the production of ATP.
4. Astrocytes appear to be needed for the formation of synapses in the CNS. Few synapses form in the
absence of astrocytes, and those are defective. Normal synapses in the CNS are ensheathed by astrocytes.
5. Astrocytes induce the formation of the blood-brain barrier. Described later
Myelin Sheath in PNS

In the process of myelin formation in the PNS, Schwann cells roll around the axon, much like a roll of
electrician’s tape is wrapped around a wire. Unlike electrician’s tape, however, the Schwann cell wrappings
are made in the same spot, so that each wrapping overlaps the previous layers.

Each Schwann cell wraps only about a millimeter of axon, leaving gaps of exposed axon between the
adjacent Schwann cells. These gaps in the myelin sheath are known as the nodes of Ranvier.

The successive wrappings of Schwann cell membrane provide insulation around the axon, leaving only the
nodes of Ranvier exposed to produce nerve impulses.

Myelinated axons of the PNS are surrounded by multiple wrappings of sheath of Schwann cells called
neurilemma. Unmyelinated axons are also surrounded by neurilemma, but they lack the multiple
wrappings of Schwann cell plasma membrane that comprise the myelin sheath.
Myelin Sheath in CNS

Myelin sheaths of the CNS are formed by oligodendrocytes.

Unlike a Schwann cell, which forms a myelin sheath around only one axon, each oligodendrocyte has
extensions, like the tentacles of an octopus, that form myelin sheaths around several axons.

The myelin sheaths around axons of the CNS give this tissue a white color; areas of the CNS that contain a
high concentration of axons thus form the white matter. The gray matter of the CNS is composed of high
concentrations of cell bodies and dendrites, which lack myelin sheaths.
Regeneration of a Cut Axon

When an axon in a peripheral nerve is cut, the distal portion of the axon that was severed from the cell
body degenerates and is phagocytosed by Schwann cells.

The Schwann cells then form a regeneration tube as the part of the axon that is connected to the cell body
begins to grow and exhibit amoeboid movement. The Schwann cells of the regeneration tube are believed
to secrete chemicals that attract the growing axon tip, and the regeneration tube helps to guide the
regenerating axon to its proper destination.

Even a severed major nerve may be surgically reconnected and the function of the nerve largely
reestablished, if the surgery is performed before tissue death occurs.

Injury in the CNS stimulates growth of axon collaterals, but central axons have a much more limited ability
to regenerate than peripheral axons. This may be due in part to the absence of a continuous neurilemma
(as is present in the PNS), which precludes the formation of a regeneration tube, and to inhibitory
molecules produced by oligodendrocytes and astrocytes in the injured CNS.

In addition to the limited ability of CNS neurons to regenerate, injury to the spinal cord has recently been
shown to actually evoke apoptosis (cell suicide) in neurons that were not directly damaged by the injury.
Blood-Brain Barrier

Capillaries in the brain, unlike other organs, do not have pores between adjacent endothelial cells. Instead,
the endothelial cells of brain capillaries are joined together by tight junctions.

Therefore, the brain cannot obtain molecules from the plasma by a nonspecific filteration. Instead, this is
done through the process of diffusion, active transport, as well as by endocytosis and exocytosis. This
feature of brain capillaries imposes a very selective blood-brain barrier.

There is evidence to suggest that the development of tight junctions between adjacent endothelial cells in
brain capillaries, forming blood-brain barrier, results from the effects of astrocytes on the brain capillaries.

BBB presents difficulties in the chemotherapy of brain diseases because drugs that could enter other
organs may not be able to enter the brain. In the treatment of Parkinson’s disease, for example, patients
who need a chemical called dopamine in the brain are often given a precursor molecule called L-dopa
because L-dopa can cross the blood-brain barrier but dopamine cannot.
Synapse

A synapse is the functional connection between a neuron and a second cell.

In CNS, other cell is a neuron. In PNS, other cell may be a neuron or an effector cell in a muscle or gland.

The latter synapses are often called myoneural, or neuromuscular, junctions.

Neuron-neuron synapses usually involve a connection between the axon of one neuron (Presynaptic) and
the dendrites, cell body, or axon of a second neuron (postsynaptic). These are called, respectively,
axodendritic, axosomatic, and axoaxonic synapses.

Most commonly, the synapse occurs between the axon of the presynaptic neuron and the dendrites or cell
body of the postsynaptic neuron.

In almost all synapses, transmission is in one direction only—from the axon of the presynaptic neuron to
the postsynaptic neuron.
Types of Synapses
1. Electrical Synapses: Gap Junctions

In order for two cells to be electrically coupled, they must be approximately equal in size and they must be
joined by areas of contact with low electrical resistance. In this way, impulses can be regenerated from one
cell to the next without interruption.

Adjacent cells that are electrically coupled are joined together by gap junctions. In gap junctions, the
membranes of the two cells are separated by only 2 nm.

Each gap junction is now known to be composed of twelve proteins known as connexins, which are
arranged hexagonally like staves of a barrel to form a water-filled pore through which ions and molecules
may pass from one cell to the next.

Gap junctions are present in cardiac muscle and some smooth muscles, where they allow excitation and
rhythmic contraction of large masses of muscle cells. Gap junctions have also been observed in various
regions of the brain. Although their functional significance in the brain is unknown, it has been speculated
that they may allow a two-way transmission of impulses (in contrast to chemical synapses, which are
always oneway).
2. Chemical Synapses

Transmission across the majority of synapses in the nervous system is one-way and occurs through the
release of chemical neurotransmitters from presynaptic axon endings. These presynaptic endings are
called terminal boutons (bouton=button) because of their swollen appearance.

Neurotransmitter molecules within the presynaptic neuron endings are contained within synaptic vesicles.

Neurotransmitter within these vesicles is released into the synaptic cleft via the process of exocytosis.

The number of vesicles that undergo exocytosis depends on the frequency of action potentials produced at
the presynaptic axon ending. Therefore, when stimulation of the presynaptic axon is increased, more of its
vesicles will release their neurotransmitters to more greatly affect the postsynaptic cell.

Voltage-regulated calcium channels are located in the axon terminal. The arrival of action potentials at the
axon terminal opens these voltage-regulated calcium channels, and it is the inward diffusion of Ca++ that
triggers the rapid fusion of the synaptic vesicle with the axon membrane and the release of
neurotransmitter through exocytosis.

In addition, Ca++ diffusing into the axon terminal activates a regulatory protein within the cytoplasm known
as calmodulin, which in turn activates an enzyme called protein kinase. This enzyme phosphorylates
specific proteins known as synapsins in the membrane of the synaptic vesicle. This action may aid the
fusion of synaptic vesicles with the plasma membrane.

Once the neurotransmitter molecules have been released from the presynaptic axon terminals, they
diffuse rapidly across the synaptic cleft and reach the membrane of the postsynaptic cell.

The neurotransmitters then bind to specific receptor proteins that are part of the postsynaptic membrane.

Binding of neurotransmitter to its receptors causes ion channels to open in the postsynaptic membrane.
Electrical activity in Neurons
Ion Gating in Axons

Ions such as Na+, K+, and others pass through ion channels in the plasma membrane that are said to be
gated channels. The “gates” are part of the proteins that comprise the channels, and can open or close the
ion channels in response to particular changes.

When ion channels are closed, the plasma membrane is less permeable, and when the channels are open,
the membrane is more permeable to an ion.

The ion channels for Na+ and K+ are fairly specific for each of these ions. It is believed that there are two
types of channels for K+; one type is always open, whereas the other type is closed in the resting cell.
Channels for Na+, by contrast, are always closed in the resting cell. The resting cell is thus more permeable
to K+ than to Na+. Some Na+ does leak into the cell; this leakage may occur in a nonspecific manner through
open K+ channels.
The Membrane Potential

There is an unequal distribution of charges across the membrane due to, permeability properties of the
plasma membrane, the presence of nondiffusible negatively charged molecules inside the cell, and the
action of the Na+/K+ pumps. As a result, the inside of the cell is negatively charged compared to the
outside. This difference in charge, or potential difference, is known as the membrane potential.

The action of the Na+/K+ pumps move Na+ and K+ against their concentration gradients. This action alone
would create a difference in the concentration of these ions across the plasma membrane.

There is, however, another reason why the concentration of Na+ and K+ would be unequal across the
membrane. Cellular proteins and the phosphate groups of ATP and other organic molecules are negatively
charged at the pH of the cell cytoplasm. These negative ions (anions) are “fixed” within the cell because
they cannot penetrate the plasma membrane. As a result, these anions attract positively charged inorganic
ions (cations) from the extracellular fluid that are small enough to diffuse through the membrane pores.
Thus, the distribution of small inorganic cations (mainly K+, Na+, and Ca++) between the intracellular and
extracellular compartments is influenced by the negatively charged fixed ions within the cell.

Since the plasma membrane is more permeable to K+ than to any other cation, K+ accumulates within the
cell more than the others as a result of its electrical attraction for the fixed anions. So, instead of being
evenly distributed between the intracellular and extracellular compartments, K+ becomes more highly
concentrated within the cell. The intracellular K+ concentration is 150 mEq/L in the human body compared
to an extracellular concentration of 5 mEq/L (mEq = milliequivalents, which is the millimolar concentration
multiplied by the valence of the ion—in this case, by 1). As a result of the unequal distribution of charges
between the inside and outside of cells, each cell acts as a tiny battery with the positive pole outside the
plasma membrane and the negative pole inside. The magnitude of this charge difference is measured in
voltage. Although the voltage of this battery is very small (less than a tenth of a volt), it is of critical
importance in such physiological processes as muscle contraction, the regulation of the heartbeat, and the
generation of nerve impulses. In order to understand these processes, then, we must first examine the
electrical properties of cells.
Equilibrium Potentials

An equilibrium potential is a theoretical voltage that would be produced across a plasma membrane if only
one ion were able to diffuse through the membrane.

What would happen if K+ were the only ion able to cross the membrane. If this were the case, K+ would
diffuse until its concentration inside and outside of a cell became stable, thus establishing an equilibrium.
In this condition, if a certain amount of K+ were to move inside the cell (by electrical attraction for the fixed
anions), an identical amount of K+ would diffuse out of the cell (down its concentration gradient). At
equilibrium, the forces of electrical attraction and of the diffusion gradient are equal and opposite.

At this equilibrium, the concentration of K+ would be higher inside the cell than outside the cell; a
concentration difference would exist across the plasma membrane that was stabilized by the attraction of
K+ to the fixed anions.

At this point we could ask, Are the fixed anions neutralized? are the charges balanced? At the K+
concentrations that are, in fact, found in the body, the answer is ‘No’. Not enough K+ is present in the cell
to neutralize the fixed anions. Therefore, at equilibrium, the inside of the cell membrane would have a
higher concentration of negative charges than the outside of the membrane.

There is a difference in charge, as well as concentration, across the membrane. The magnitude of the
difference in charge, or potential difference, on the two sides of the membrane under these conditions is
90 millivolts (mV). (+or –) placed in front of this number indicates the polarity within the cell. This is shown
with a negative sign (as –90 mV) to indicate that the inside of the cell is the negative pole.

The potential difference of –90 mV, which would be developed if K+ were the only diffusible ion, is called
the K+ equilibrium potential (EK).
Nernst Equation
The Nernst equation allows this theoretical equilibrium potential to be calculated for a particular ion when
its conconcentrations are known. The following simplified form of the equation is valid at a temperature of 37°C.
Ex
=
61 log [Xo]/[Xi]
z
Ex = equilibrium potential in millivolts (mV) for ion x
Xo = concentration of the ion outside the cell
Xi = concentration of the ion inside the cell
z = valence of the ion (+1 for Na+ or K+)
If we substitute K+ for X, this is indeed the case. In reality, the concentration of K+ inside the cell (5 mEq/L)
is actually 30 times greater than outside (150 mEq/L). Thus,
EK
=
61 log 5 mEq/L
=
-90 mV
Z
150 mEq/L
This means that a membrane potential of 90 mV, with the inside of the cell negative, would be required to
prevent the diffusion of K+ out of the cell. The concentration of Na+ in the ECF is 145 mEq/L, whereas its
concentration inside cells is only 12 mEq/L. Thus,
ENa
=
61 log 145 mEq/L =
+60 mV
Z
12 mEq/L
This means that a membrane potential of 60 mV, with the inside of the cell positive, would be required to
prevent the diffusion of Na+ into the cell. Note that, using the Nernst equation, the equilibrium potential for a
cation has a negative value when Xi is greater than Xo and positive value when Xi is less than Xo.
Note: Intracellular and extracellular concentrations of Ca++ = 9mM & 125mM
“
”
”
”
Cl- = 0.0001 & 2.5 mM
Resting Membrane Potential

A membrane potential of +60 mV would prevent the diffusion of Na+ into the cell, while a membrane
potential of –90 mV would prevent the diffusion of K+ out of the cell. In addition Ca++, and Cl- also
contribute to the resting membrane potential. Thus, the membrane potential is somewhere in between
the individual values. We will call this the resting membrane potential to distinguish it from the theoretical
equilibrium potentials. The actual value of the resting membrane potential depends on two factors:
1. The ratio of the concentrations (Xo /Xi) of each ion on the two sides of the plasma membrane.
2. The specific permeability of the membrane to each different ion.

This has two important implications:
1. For any given ion, a change in its concentration in the extracellular fluid will change the resting
membrane potential—but only to the extent that the membrane is permeable to that ion. Because the
resting membrane is most permeable to K+, a change in the extracellular concentration of K+ has the
greatest effect on the resting membrane potential. This is the mechanism behind the fact that “lethal
injections” are of KCl (raising the extracellular K+ concentrations and depolarizing cardiac cells.).
2. A change in the membrane permeability to any given ion will change the membrane potential. This fact
is central to the production of nerve and muscle impulses. Most often, it is the opening and closing of Na+
and K+ channels that are involved, but gated channels for Ca++ and Cl– are also very important in physiology.
The resting membrane potential of most cells in the body ranges from –65 mV to –85 mV (in neurons it
averages –70 mV). This value is close to the EK, because the resting plasma membrane is more permeable
to K+ than to other ions. During nerve and muscle impulses, however, the permeability properties change.
An increased membrane permeability to Na+ drives the membrane potential toward ENa (+60 mV) for a
short time. This is the reason that the term resting is used to describe the membrane potential when it is
not producing impulses.
Role of the Na+/K+ Pumps
Since the resting membrane potential is less negative than EK, some K+ leaks out of the cell. The cell is not
at equilibrium with respect to K+ and Na+ concentrations. Nonetheless, the concentrations of K+ and Na+ are
maintained constant because of the constant expenditure of energy in active transport by the Na+/K+ pumps. The
Na+/K+ pumps act to counter the leaks and thus maintain the membrane potential. Actually, the Na+ /K+ pump does
more than simply work against the ion leaks; since it transports three Na+ out of the cell for every two K+ that it
moves in, it has the net effect of contributing to the negative intracellular charge. This electrogenic effect of the
pumps adds approximately 3 mV to the membrane potential. As a result of all of these activities, a real cell has (1)
a relatively constant intracellular concentration of Na+ and K+ and (2) a constant membrane potential (in the
absence of stimulation) in nerves and muscles of –65 mV to –85 mV.
Conduction of Nerve Impulse

Resting membrane potential in a neuron is equal to -70 mV

An appropriate stimulus results in the opening of gated ion channels in the cell membrane of a neuron
leading to changes in permeability of the membrane to certain ions.

Two broad categories of gated ion channels have been described: voltage-regulated and chemically
regulated. Voltage-regulated channels are found primarily in the axons; chemically regulated channels are
found in the postsynaptic membrane. Voltage-regulated channels open in response to depolarization;
chemically regulated channels open in response to the binding of postsynaptic receptor proteins to their
neurotransmitter.

Depolarization: Opening of Na+ channels results in the influx of Na+, thus, the inside of the postsynaptic
membrane becomes less negative (↓ in polarization). As a result of influx of Na+ membrane potential
changes from -70mV to +30mV. This depolarization is called an excitatory postsynaptic potential (EPSP)
because the membrane potential moves toward threshold.

Repolarization: A fraction of a second after the Na+ channels open, they close again. Just before they do,
the depolarization stimulus causes the K+ gates to open. This makes the membrane more permeable to K+
than it is at rest, and K+ diffuses down its concentration gradient out of the cell. The K + gates will then close
and the permeability properties of the membrane will return to what they were at rest. Since K+ is
positively charged, the diffusion of K+ out of the cell makes the inside of the cell less positive, or more
negative, and acts to restore the original resting membrane potential of –70 mV. This process is called
repolarization and represents the completion of a negative feedback loop.

These changes in Na+ and K+ diffusion and the resulting changes in the membrane potential they produce
constitute an event called the action potential, or nerve impulse.

Once an action potential has been completed, the Na +/K+ pumps will extrude the extra Na+ that has
entered the axon and recover the K+ that has diffused out of the axon.

Hyperpolarization Certain other stimuli or binding of an inhibitory neurotransmitter such as GABA may
result in opening of Cl- channels. This will result in influx of Cl- down its concentration gradient leading to
further increase in membrane polarity—the inside of the postsynaptic membrane becomes more negative.
This hyperpolarization is called an inhibitory postsynaptic potential (IPSP) because the membrane potential
moves farther from threshold.

Excitatory postsynaptic potentials stimulate the postsynaptic cell to produce action potentials, and
inhibitory postsynaptic potentials antagonize this effect.

Action potentials occur in axons, where the voltagegated channels are located, whereas EPSPs occur in the
dendrites and cell body.

Unlike action potentials, EPSPs have no threshold; the ACh released from a single synaptic vesicle produces
a tiny depolarization of the postsynaptic membrane. When more vesicles are stimulated to release their
ACh, the depolarization is correspondingly greater. EPSPs are therefore graded in magnitude, unlike all-ornone action potentials.

Once the first action potentials are produced, they will regenerate themselves along the axon as previously
described. In summary, the following sequence of events occurs:
1. An excitatory neurotransmitter produces a depolarization. (An inhibitory neurotransmitter has the
opposite effect—it causes a hyperpolarization.)
2. The depolarization causes the opening of voltageregulated ion channels.
3. Opening of voltage-regulated channels in the initial segments of axon produces action potentials.
4. The action potential serves as the depolarization stimulus for the next region and is regenerated along
the axon or muscle cell.
All or None Law Action potential does not normally become more positive than +30 mV because the Na+
channels quickly close and the K+ channels open. The length of time that the Na+ and K+ channels stay open is
independent of the strength of the depolarization stimulus. The amplitude (size) of action potentials is therefore
all or none. Since the change from –70 mV to +30 mV and back to –70 mV lasts only about 3 msec, the image of an
action potential on an oscilloscope screen looks like a spike. Action potentials are therefore sometimes called
spike potentials.
Coding for Stimulus Intensity Because action potentials are all-or-none events, a stronger stimulus cannot
produce an action potential of greater amplitude. The code for stimulus strength in the nervous system is not
amplitude modulated (AM). When a greater stimulus strength is applied to a neuron, identical action potentials
are produced more frequently (more are produced per second). Therefore, the code for stimulus strength in the
nervous system is frequency modulated (FM).
Refractory Periods As action potentials are produced with increasing frequency, the time between successive
action potentials will decrease—but only up to a minimum time interval. The interval between successive action
potentials will never become so short as to allow a new action potential to be produced before the preceding one
has finished.
Absolute refractory period
During the time that a patch of axon membrane is producing an action potential, it is incapable of responding—or
refractory—to further stimulation. If a second stimulus is applied during most of the time that an action potential
is being produced, the second stimulus will have no effect on the axon membrane. The membrane is thus said to
be in an absolute refractory period; it cannot respond to any subsequent stimulus.
Relative refractory period
If a second stimulus is applied while the K+ gates are open (and the membrane is in the process of repolarizing),
the membrane is said to be in a relative refractory period. During this time, only a very strong depolarization can
overcome the repolarization effects of the open K+ channels and produce a second action potential.
Neurotransmitters
Acetylcholine

Acetylcholine (ACh) is used as an excitatory neurotransmitter by some neurons in the CNS and by somatic
motor neurons at the neuromuscular junction.

At autonomic nerve endings, ACh may be either excitatory or inhibitory, depending on the organ involved.

The varying responses of postsynaptic cells to the same chemical can be explained by the fact that
different postsynaptic cells have different subtypes of ACh receptors. These receptor subtypes can be
specifically stimulated by particular toxins, and they are named for these toxins.
1. Nicotinic ACh receptors. The are so named because they can also be activated by nicotine. These are found
in specific regions of the brain, in autonomic ganglia, and in skeletal muscle fibers. The release of ACh from
somatic motor neurons and its binding to nicotinic receptors, for example, stimulates muscle contraction.
2. Muscarinic ACh receptors. The are so named because they can also be activated by muscarine (a drug
derived from certain poisonous mushrooms). These are found in the plasma membrane of smooth muscle
cells, cardiac muscle cells, and the cells of particular glands. Thus, the activation of muscarinic ACh receptors
over there is required for the regulation of the cardiovascular system, digestive system, and others.
Chemically Regulated Channels
The actions of Ach on the nicotinic and muscarinic subtypes of the ACh receptors can be illustrated as,
Ligand-Operated Channels

In this case, the ion channel is run by the receptor itself. The ion channel is directly opened by the binding
of the receptor to the neurotransmitter. Such is the case when ACh binds to its nicotinic ACh receptor.

This receptor consists of polypeptide subunits that enclose the ion channel. These subunits contain AChbinding sites, and the channel opens when both sites bind to ACh.

The opening of this channel permits the simultaneous diffusion of Na+ into and K+ out of the postsynaptic
cell. The effects of the inward flow of Na+ predominate, however, because of its steeper electrochemical
gradient. This produces the depolarization of an excitatory postsynaptic potential (EPSP).
G-Protein-Operated Channels

The muscarinic ACh receptors are formed from only a single subunit, which can bind to one ACh molecule.

Unlike the nicotinic receptors, these receptors do not contain ion channels. The ion channels are separate
proteins located at some distance from the muscarinic receptors. Binding of ACh to the muscarinic
receptor causes it to activate a complex of proteins in the cell membrane known as G-proteins—so named
because their activity is influenced by guanosine nucleotides (GDP and GTP).

There are three G-protein subunits, designated alpha, beta, and gamma. In response to the binding of ACh
to its receptor, the alpha subunit dissociates from the other two subunits, which stick together to form a
beta-gamma complex.

Depending on the specific case, either the alpha subunit or the beta-gamma complex then diffuses through
the membrane until it binds to an ion channel, causing the channel to open. A short time later, the Gprotein alpha subunit (or beta-gamma complex) dissociates from the channel and moves back to its
previous position. This causes the ion channel to close.

The binding of ACh to its muscarinic receptors indirectly affects the permeability of K+ channels. This can
produce hyperpolarization in some organs (if the K+ channels are opened) and depolarization in other
organs (if the K+ channels are closed).

It is the beta-gamma complex that binds to the K+ channels in the heart muscle cells and causes these
channels to open. This leads to the diffusion of K+ out of the postsynaptic cell (concentration gradient). As a
result, the cell becomes hyperpolarized, producing an inhibitory postsynaptic potential (IPSP) and slow the
rate of beat.

There are cases in which the alpha subunit is the effector. In the smooth muscle cells of the stomach, the
binding of ACh to its muscarinic receptors causes a different type of G-protein alpha subunit to dissociate
and bind to the K+ channels. In this case, however, the binding of the G-protein subunit to the K+ channels
causes the channels to close rather than to open. As a result, the outward diffusion of K+, which occurs at
an ongoing rate in the resting cell, is reduced to below resting levels. Since the resting membrane potential
is maintained by a balance between cations flowing into the cell and cations flowing out, a reduction in the
outward flow of K+ produces a depolarization. This depolarization produced in these smooth muscle cells
results in contractions of the stomach.

The ACh-receptor complex quickly dissociates. Free Ach must be inactivated very soon after it is released.
The inactivation of ACh is achieved by means of an enzyme called acetylcholinesterase, (AchE) which is
present on the postsynaptic membrane or immediately outside the membrane, with its active site facing
the synaptic cleft.
Monoamines as Neurotransmitters

Epinephrine, norepinephrine, dopamine, and serotonin are in the chemical family known as monoamines.

Serotonin is derived from the amino acid tryptophan. Epinephrine, norepinephrine, and dopamine are
derived from the amino acid tyrosine and form a subfamily of monoamines called the catecholamines.

Epinephrine (also called adrenaline) is a hormone secreted by the adrenal gland, not a neurotransmitter,
while norepinephrine functions both as a hormone and a neurotransmitter.

Like ACh, monoamine neurotransmitters are released by exocytosis from presynaptic vesicles, diffuse
across the synaptic cleft, and interact with specific receptors in the membrane of the postsynaptic cell.

The monoamine neurotransmitters do not directly cause opening of ion channels in the postsynaptic
membrane. Instead, these neurotransmitters act by means of an intermediate regulator, known as a
second messenger. In the case of catecholamines for synaptic transmission, this second messenger is a
compound known as cyclic adenosine monophosphate (cAMP). Although other synapses can use other
second messengers. Binding of norepinephrine, for example, with its receptor in the postsynaptic
membrane stimulates the dissociation of the G-protein alpha subunit from the others in its complex. This
subunit diffuses in the membrane until it binds to an enzyme known as adenylate cyclase (also called
adenylyl cyclase). This enzyme converts ATP to cyclic AMP (cAMP) and pyrophosphate (two inorganic
phosphates) within the postsynaptic cell cytoplasm. cAMP in turn activates another enzyme, protein
kinase, which phosphorylates (adds a phosphate group to) other proteins. Through this action, ion
channels are opened in the postsynaptic membrane.

The stimulatory effects of these monoamines, like those of ACh, must be quickly inhibited so as to maintain
proper neural control. The inhibition of monoamine action is due to (1) reuptake of monoamines into the
presynaptic neuron endings, (2) enzymatic degradation of monoamines in the presynaptic neuron endings
by monoamine oxidase (MAO), and (3) the enzymatic degradation of catecholamines in the postsynaptic
neuron by catechol-O-methyltransferase (COMT).

Physiological functions attributed to serotonin include a role in the regulation of mood and behavior,
appetite, and cerebral circulation.

Serotonin’s diverse functions are related to the fact that there are a large number of different subtypes of
serotonin receptors— over a dozen are currently known.
Dopamine as a Neurotransmitter

Neurons that use dopamine as a neurotransmitter are called dopaminergic neurons. The cell bodies of
dopaminergic neurons are highly concentrated in the midbrain. Their axons project to different parts of the
brain and can be divided into two systems: the nigrostriatal dopamine system, involved in motor control,
and the mesolimbic dopamine system, involved in emotional reward.
Nigrostriatal Dopamine System

The cell bodies of the nigrostriatal dopamine system are located in a part of the midbrain called the
substantia nigra (“dark substance”) because it contains melanin pigment. Neurons in the substantia nigra
send fibers to a group of nuclei known collectively as the corpus striatum because of its striped
appearance— hence the term nigrostriatal system. These regions are part of the basal nuclei (large masses
of neuron cell bodies deep in the cerebrum involved in the initiation of skeletal movements).
Mesolimbic Dopamine System

The mesolimbic dopamine system involves neurons that originate in the midbrain and send axons to
structures in the forebrain that are part of the limbic system. The dopamine released by these neurons
may be involved in behavior and reward.
Amino Acids as Neurotransmitters
The amino acids glutamic acid and aspartic acid function as excitatory neurotransmitters in the CNS.
Glutamic acid (or glutamate), indeed, is the major excitatory neurotransmitter in the brain, producing excitatory
postsynaptic potentials (EPSPs). Research has revealed that each of the glutamate receptors encloses an ion
channel, similar to the arrangement seen in the nicotinic ACh receptors.
The amino acid glycine is inhibitory; instead of depolarizing the postsynaptic membrane and producing an
EPSP, it hyperpolarizes the postsynaptic membrane and produces an inhibitory postsynaptic potential (IPSP). The
inhibitory effects of glycine are very important in the spinal cord, where they help in the control of skeletal
movements. Flexion of an arm, for example, involves stimulation of the flexor muscles by motor neurons in the
spinal cord. The motor neurons that innervate the antagonistic extensor muscles are inhibited by IPSPs produced
by glycine released from other neurons.
The neurotransmitter gamma-aminobutyric acid (GABA) is a derivative of another amino acid, glutamic
acid. GABA is the most prevalent neurotransmitter in the brain; in fact, as many as one-third of all the neurons in
the brain use GABA as a neurotransmitter. Like glycine, GABA is inhibitory—it hyperpolarizes the postsynaptic
membrane by opening Cl– channels. Also, the effects of GABA, like those of glycine, are involved in motor control.
Neuropeptide Y
Neuropeptide Y has been shown to have a variety of physiological effects, including a role in the response
to stress, in the regulation of circadiac arhythmias, and in the control of the cardiovascular system. Neuropeptide
Y has been shown to inhibit the release of the excitatory neurotransmitter glutamate in a part of the brain called
the hippocampus. This is significant because excessive glutamate released in this area can cause convulsions.
Neuropeptide Y is a powerful stimulator of appetite. Conversely, inhibitors of neuropeptide Y that are injected into
the brain inhibit eating.
Endocannabinoids as Neurotransmitters
The brain also produces compounds with effects similar to the active ingredient in marijuana—Δ9tetrahydrocannabinol (THC). These endogenous cannabinoids, or endocannabinoids, are neurotransmitters that
bind to the same receptor proteins in the brain as does THC from marijuana. The endocannabinoids, like the
endogenous opioids, are believed to act as analgesics. Unlike the polypeptide opioids, however, the
endocannabinoids are lipids.