The Physiology of Neuronal

Functions
neuronal morphology
neuronal circuits
membrane potentials
passive electrical properties of
membranes
electrochemical potentials
the generation of the membrane
resting potential
stimulation of the action potential
ionic basis of the action potential
the voltage-gated Na
+
channel
References: p. 113-128; 131-137
Central nervous system (CNS): neurons of the brain and
the nerve cord (the spinal cord in vertebrates)
Peripheral nervous system (PNS): neurons that connect
the CNS to all target tissues
Nervous systems
Morphology
of neurons
All neurons have the
soma, one axon, and
numerous dendrites. The
complexity of structure
is related to function,
not phylogeny.
Neuronal morphology
Soma
cell body
site of metabolism and cell
maintenance
may receive stimuli from
other neurons
Dendrites
extensions of the soma
receive stimuli
receive signals form other
neurons
typical neuron can have
100s-1000s
Axon
conducts signals away from the cell body and toward the
axon terminal
only one per neuron
may branch at the axon terminal
during the development of the nervous system: the axon
extends from the soma toward the target cell(s) following
migratory cues
when the target is reached, specific junctions are formed
Neuronal morphology
Cell body extensions and their interactions with other cells
establish a cell polarity:
dendrites: toward soma
axon: away from soma
Neuronal polarity
Example: skin mechanoreceptors (touch receptors) signals
travel from dendrites near skin to soma, then from soma
to axon terminals near the spinal cord (next illustration)
Transmission of signals
between neurons in a
simple neuronal circuit
Sensory neurons (afferent neurons):
receive external stimuli and
transmit them to the CNS.
Interneurons: connections within
the CNS.
Motor neurons (efferent neurons):
relays the signal to the tissue
that will elicit the response.
A simple neuronal circuit
The reflex arch in the cockroach:
afferent neuron: wind receptor
a giant interneuron
within the CNS
efferent neuron: leg
motor neuron
Note: locations
of the soma.
In any neural connection there
is a presynaptic cell (the neuron
that transmits the signal) and a
postsynaptic cell (the target,
which may be another neuron or
a different cell type).
Transmission of electrical
signals between neurons
Synapses: the junctions between
both cells.
Graded signals: through the soma
vary in amplitude
the strength of the signal depends
on the strength of the stimulus
lose intensity as they propagate
All-or-none signals: through the
axon
invariant amplitude
initiate in response to graded signals
once initiated, they propagate down
the axon without loss of signal
intensity
Transmission of electrical
signals within neurons
The dendrites and the soma receive neurotransmitters
(chemical signals) from presynaptic terminals (the axon
terminals from presynaptic neurons).
chemical signals are then converted into electrical signals
when ion currents in the synapse region flow into the cell
these ion currents (graded signals) travel through the soma
and are integrated at the spike initiation zone
the neuron then initiates its own electrical signal: the action
potential (AP, an all-or-none signal)
the action potential then travels down the axon and away
from the soma without losing its intensity
the signal reaches the axon terminal
the signal is converted back into a chemical signal when a
neurotransmitter is secreted into the next synapse
Transmission of electrical signals within the neuron
Transmission of electrical
signals within neurons
The neurons ability to transmit
a graded signal depends on the
passive electrical properties of
its membrane. The neurons
ability to initiate an all-or-none
signal, and its ability to transmit
it without signal loss, depend
on the active electrical properties
of its membrane.
The nature of electrical signals in neurons
Electric potential:
the concentration of ions on one side of the membrane
electrostatic force: potential energy (why?)
Membrane potential:
the difference in ionic electric potentials between the two
sides of a membrane
Result: a voltage across the membrane (V
m
), measured in
millivolts (mV)
The ion gradients across the membrane
of a typical mammalian cell
The ion gradients across the membrane maintains osmotic
balance and are also necessary for many physiological
functions.
Membrane-targeted antibiotics transport ions across the cell
membrane and destroy ionic gradients that are essential to
the life of the cells
Ionophores:
Valinomycin is a small ring molecule that binds K
+
in its
hydrophilic interior, shielding its charge from the
surrounding environment
the outside region of the molecule is nonpolar, thus
facilitating its crossing of the hydrophobic interior of the
lipid membrane
Channel formers:
Gramicidins are dimers of linear peptides that insert
themselves into lipid bilayers and allow the free passage
of H
+
, K
+
, and Na
+
ions
Cystic fibrosis
Cystic fibrosis is caused by a mutation in an ATP-dependent
Cl
-
transport, which alters the normal ionic gradients in
several types of epithelial cells.
this results in the abnormal production of thick, sticky
mucous secretions by epithelial cells lining the
respiratory and intestinal tracts (Why?)
treatment may extend the survival of affected individuals to
about 30 years, but the disease is ultimately fatal, with
lung disease being responsible for 95% of mortality
The ATP-dependent Cl
-

transport
70% of the point mutations
that cause cystic fibrosis
disrupt the folding of the
protein, resulting in
defective Cl
-
transport.
Na
+
, K
+
, Ca
2+
, and Cl
-
gradients maintain membrane
voltages in all living cells, but:
only two types of cells are able to respond to changes in
membrane voltage: neurons and muscle cells
only neurons and muscle cells are excitable cells
The voltage across a membrane
Luigi Galvani
(1737-1798)
Italian physicist
Luigi Galvani was looking for the animal electricity that
activated the muscles of his dissected frog specimens.
he devised an electrical circuit: a muscle cell touched by a
nerve and a zinc rod, and a different metal rod (cooper)
that linked the nerve and the zinc rod (a)
he then observed that muscle cells contracted when the two
dissimilar rods touched (circuit completed)
Alessandro Volta (1792) suggested that the metal rods
provided an outside energy source that excited the cells
Carlo Matteucci demonstrated that excitable tissues produce
electric currents (b)
Luigi Galvanis experiments (1791)
Luigi Galvanis experiments (1791)
Carlo Matteuccis experiments
V
m
can be recorded as the difference in electric potentials
detected by a recording glass microelectrode and a
reference electrode.
no difference when both electrodes are in the saline bath
Measuring membrane potential
when the recording electrode penetrates cell, the difference
in electric potentials between the two sides of the
membrane is recorded as a voltage (V
m
)
V
m
(membrane voltage) of living cells have negative values:
higher concentration of negative ions on the cytosolic side
of the membrane (inside the cell)
Measuring membrane potential
Membrane potential
The membrane potential of living cells is defined as the
cytosolic potential relative to the extracellular potential
(extracellular potential is conventionally defined as zero).
steady inside-negative potential: resting potential (V
rest
)
all cells have a V
rest
between -20 mV and -100 mV
due to the passive electrical properties of the membran
Electrical Resistance (R): impermeability to ions.
Electrical Conductance (g): permeability to ions due to open
ion channels.
Passive electrical properties of the cell membrane
the resistive current (I
r
) will be higher if R is low (when ion
channels open)
R=1/g
Capacitance: the ability to store electric charges (C
m
).
the lipid bilayer is impermeable to ions but is very thin,
therefore:
ionic charges on both sides of the membrane can interact
if there is an excess of positive charges on the extracellular
side: they will be displaced toward the membrane, they
will attract anions on the other side, and cations on the
cytoplasm will be repelled from the membrane
effect: a capacitative current (I
c
)
Passive electrical properties of the cell membrane
Capacitance: C
m

Capacitative
current: I
c

The cell membrane as a capacitor
Membrane voltage changes in response to
stimulating currents
Stimulus current: an ion flow through the cell membrane that
can change its resting potential.
this current can be experimentally applied using a current
electrode
Membrane voltage
changes in response to
stimulating currents
Deviations from the resting
potential in response
to applied currents:
small negative stimulus
current: a small
hyperpolarization of
the membrane (1 & 2)
small positive stimulus
current: a small
depolarization of
the membrane (3)
But:
if V
m
reaches the
threshold potential:
an action potential
(AP) is fired (4)
Membrane voltage
changes in response to
stimulating currents
(this happens only
in excitable cells)
Whats wrong with
this figure?
The DV
m
resulting from
a subthreshold stimulus
should be sustained for
as long as the stimulus
current is applied.
Membrane voltage
changes in response to
stimulating currents
capacitance and conductance/resistance are the passive
electrical properties of the membrane
they give the membrane its ability for time-dependent
responses to stimulation and voltage changes
they depend on the membrane potential (V
m
)
Summary
How is the membrane potential generated?
Passive electrical properties of the membrane
Electrochemical potential defines the potential difference
across the plasma membrane. It is dependent on two
features of cells:
1. the concentrations of certain ions on the cytosolic side
of the membrane are different from the extracellular
side of the membrane
2. membranes are selectively permeable to ions due to
the presence of selective ion channels
Electrochemical potential
A chamber filled with KCl, with two compartments separated
by a membrane that is permeable to K
+
but not to Cl
-
equal movement of K
+
in both directions but no net
changes in K
+
concentration
equal distribution of charges: no potential difference (V
m
=0)
If KCL concentration in compartment I is increased
K
+
will tend to move to compartment II (due to the K
+

concentration gradient)
this will generate a K
+
gradient and a voltage across the
membrane
the resulting electromotive force (emf) will tend to drive K
+

back to compartment I
when no more net K
+
flow occurs: electrochemical
equilibrium, due to both driving forces, which occurs
at the equilibrium potential
If KCL concentration
in compartment I
is increased
Summary of definitions
Electrochemical equilibrium:
the state at which the concentration gradient of an ion across
a membrane is precisely balanced by the electromotive
force across the membrane in the opposite direction
not net flow of the ion occurs
it is not the state in which the concentrations of the ion on
both sides of the membrane are equal
Equilibrium potential (E
x
):
the V
m
at which an ionic species that can diffuse across the
membrane is in electrochemical equilibrium
example: the equilibrium potential for K
+
is E
K
The resting membrane potential (V
rest
) in cells is
maintained at the expense of metabolic energy.
because of this, V
rest
is a steady state potential (not an
equilibrium potential)
V
rest
gives the membrane its passive electrical properties
(capacitance and conductance/resistance)
The generation of the membrane potential
in biological membranes
Generation of the membrane resting potential
The ions channels responsible for the steady state potential
are the Na
+
/K
+
pump (requires energy) and the
K
+
leak channel (does not require energy).
The Na
+
/K
+
pump
hydrolyzes ATP to transport 3 Na
+
s out of the cell
and 2 K
+
s to the cytoplasm
result: unequal ionic distribution (an electrochemichal
gradient)
The K
+
leak channel
allows some K
+
to flow back through the membrane
determined by:
1. concentration gradient (K
+
inside)
2. electrical gradient (Na
+
emf from outside)
The Na
+
/K
+

pump generates
the membrane
resting potential
Active electrical properties of the membrane
The action potential
The action potential (AP) is a sudden and transient change
in the cell membrane potential: V
m
becomes positive.
occurs when voltage gated Na+ channels on the excitable
membrane open, allowing the flow of Na
+
into the cell
these channels are not the same as the Na
+
/K
+
pump that
generate the electrochemichal gradient
the AP is an all-or-none signal: its amplitude is invariable*
APs can only occur in excitable cells: neurons and muscle
cells
the repolarization of the membrane following an AP
depends on voltage-gated K+ channels
Sequence of events:
at rest, all voltage-gated channels are closed
when Na
+
voltage-gated channels open: depolarization
(rising phase)
Na
+
channels then become inactive and K
+
voltage-gated
channels (not pictured) open: return (falling phase)
after hyperpolarization, K
+
channels close and Na
+
channels
return to the closed conformation
Ionic basis of the action potential
Voltage gated Na
+
channels & the action potential
V
rest
~ -70 mV
Rising phase:
Na
+
conductance (g
Na
) increases
Na
+
flows in

(depolarization)
Falling phase:
g
Na
decreases
K
+
conductance (g
K
) increases
as the inward Na
+
current decreases, an outward flow of K
+

occurs, resulting in hyperpolarization
After the AP:
g
K
decreases
as the K
+
current decreases, the membrane returns to V
rest
Changes in V
m
and ionic conductances
during an action potential
Changes in V
m
and
ionic conductances during
an action potential
Ion cunductances (g)
Membrane polarity (V)
(not the direction of
ion currents)
The threshold potential is defined as the V
m
at which an AP is
triggered 50% of the times.
Threshold potential
if a stimulating current is not intense enough to fire an AP
(1 & 2, subthreshold stimuli), the resulting DV
m
is only
sustained for as long as the stimulus current is applied but
will return to V
rest
as soon as the stimulus ends
an AP response will continue without the stimulus current
overshoot: the period during which the membrane polarity is
reversed and the interior is more positive
membrane will quickly return directly to V
rest
, or:
it may go below V
rest
: hyperpolarization (undershoot), then
slowly return to V
rest

a threshold current (3) triggers APs but can sometimes result
in a local response (an abortive AP)
The action potential is fired when the membrane reaches the
threshold potential in response to a stimulating current
The refractory periods after an action potential
Immediately following an AP, a second AP is not possible
during the absolute refractory period (ARP).
the first stimulus current triggers an AP, but
a second stimulus will not trigger an AP if applied within
the absolute refractory period
during the relative refractory period (RRP), an AP may be
triggered but only if the stimulus is more intense
the amplitude of any AP triggered during the relative
refractory period will be smaller
The refractory periods
after an action potential
Excitability of the
membrane:
zero during ARP
increases during RRP
(textbook toilet!)
The neuron threshold potential can increase in response
to slowly increasing subthreshold stimuli
Accommodation
Accommodation to sustained stimulation
Phasic accommodation is a rapid accommodation to a
sustained stimulus current.
only 1-2 APs will occur, and only when the stimulus begins
Lowered accommodation response
Tonic accommodation is slow accommodation.
APs will be fired repeatedly during stimulation, but with
decreasing frequency
In the soma and the dendrites,
a stimulus current elicited by
a presynaptic cell induces a
voltage change (a graded
signal) that propagates until it
reaches the spike initiation
zone. If the current is still
strong enough when it reaches
the spike initiation zone, it will
induce APs (all-or- nothing
signals) that will propagate
down the axon.
Transmission of electrical
signals within neurons
Propagation of the action potential
The opening and closing of voltage-gated Na
+
channels
along the axon is sequential.
the current that flows through one Na
+
channel (or through
a local group of Na
+
channels) provides the stimulus
(voltage change) to open the next channels
electrodes can measure membrane voltage at different
points along an axon
Propagation of the action potential
Propagation of an action potential along an axon
orange arrows: Na
+
flow
blue box: depolarized region
Propagation of an action potential along an axon
orange arrows: Na
+
flow
blue box: depolarized region
absolute: all local voltage-gated Na
+
channels are inactive
relative: local voltage-gated Na
+
channels are returning to
the closed conformation and some voltage-gated K
+

channels remain open
in an excitable membrane (a membrane that can elicit an
all-or-none response): all voltage-gated Na
+
and K
+

channels are closed
The refractory periods after an action potential