Chapter 9
Signal Transduction Mechanisms: Nerve Cells
I Nervous System
A. Components
1. central nervous system (CNS)
a. brain
b. spinal cord
2. peripheral nervous system (PNS)
a. somatic nervous system
1) voluntary muscle control
b. autonomic nervous sytem
1) involuntary activities
a) cardiac muscle
b) smooth muscles of gastrointestinal tract
c) smooth muscles of blood vessels
d) secretory glands
e) sensory input
-vision, touch, hearing, temperature
3. will study the systems in physiology
B. two basic types of nerve cells
1. neurons
a. sensory neurons
1) diverse group of cells
2) specialized for detection of stimuli
3) examples
a) photoreceptors in retina
b) olfactory neurons
c) pressure sensitive neurons
d) temperature sensitive neurons
e) pain sensitive neurons
b. motor neurons
1) transmit signals from CNS to muscles or glands
c. interneurons
1) transfer signals from one nerve cell to another
2. glial cells = neuroglial cells
a. nonexcitable, supportive cells in nervous system
b. eg: astrocytes
1) found vertebrate CNS
2) control access of blood vessels to
extracellular fluid surrounding
CNS nerve cells
3) forms the "blood-brain barrier"
c. eg: oligodendrocytes
1) found vertebrate CNS
2) form an insulating myelin sheath
around CNS neurons
d. eg: Schwann cells
1) found peripheral nervous system
2) form an insulating myelin sheath
around peripheral neurons
II Nerve Cell Structure
A. Typical Motor Neuron Structure
1. cell body
a. like other cells
2. processes = extensions
a. two types of processes
1) dendrites
a) receive and combine signals
from other neurons
b) usually short compared to axons
c) bring signals TO cell body
2) axons
a) conduct signals AWAY from cell body
b) cytoplasm inside axon called axoplasm
c) surrounded by myelin sheath of Schwann cells
d) can be very long
-sometimes many meters in large vertebrates
e) a "nerve" = a bundle of axons
-eg: see a frog sciatic nerve
-eg: see a cross section of frog sciatic nerve
-see cross section of
many individual axons
-note scale: each axon about
10 um in diameter
f) axons end in terminal branches with terminal bulbs
-bulbs transmit signal to muscle cell/gland/dendrite
g) junction between the terminal
bulb and muscle/gland = synapse
-neurons usually have many synapses
with many other neurons
B. Structure of Other Neurons
1. quite variable
2. sensory neurons
a. only one process travels to interneurons
3. see many other neuron shapes (Fig 9-4)
III Membrane Potential = Vm
A. unbalanced electric charge distribution
from one side of membrane to other
1. eg: typical mammalian cell
2. more + charges on one side than the other
3. leads to an electric potential = membrane
potential (Vm) across membrane
a. typical cell has membrane potential
of about 70 mV (inside negative)
4. membrane potential is the force ("pressure") that
tends to move ions such that the electric charges
become balanced
a. cell must do work (expend energy) to
maintain an ongoing membrane potential
b. hence: many dyes that indentify living cells
really measure presence of membrane potential
-see live-dead giardia cells
-green cells are alive (membrane potential okay)
-red cells a dead (no membrane potential)
-see examples at Molecular Probes-Gallery-Viability stains
B. electrical excitability
1. some cells can rapidly change Vm
a. eg: nerve, muscle & some glandular cells
2. rapid change Vm = action potential
a. Vm changes from inside negative
to inside positive and back
to inside negative in about 1 millisecond
3. used to transmit electrical signal down an axon
C. resting potential
1. due to different concentrations of ions in
cytoplasm and suspending medium
2. suspending medium has high [NaCl]
3. cytoplasm has high [K+]
a. due to Na/K pump
b. counter balancing anions are
mostly membrane impermeable
macromolecules (proteins, nucleic acids, etc)
c. presence of membrane impermeable
anions is main cause of membrane potential
d. K+ diffuses out of cell, down concentration gradient
e. as K+ leaves, the macromolecules with their
many negative charges remain
f. leads to development of membrane potential
g. membrane potential pulls K+ back toward cell
h. membrane potential keeps K+ from fully
equilibrating across membrane
4. ion concentration gradients
a. ions and molecules diffuse from where they
are more concentrated to where they
are less concentrated
(1) K+ has a tendency to diffuse out of cell
-ion impermeable membrane prevents
diffusion through hydrophobic barrier
-membrane has K+ channels that "leak"
-K+ leakage much greater than Na+ leakage
(2) Na+ has a tendency to diffuse into cell
-ion impermeable membrane prevents
diffusion through hydrophobic barrier
-membrane has Na+ channels that "leak"
- Na+ leakage much less than K+ leakage
5. electroneutrality
a. whole system remains electrically neutral
(1) equal numbers of + and - charges
(2) but, distribution of +/- charges not uniform
(a) more - charges inside cell than
counterbalancing + charges
(b) more + charges outside cell than
counterbalancing - charges
(3) results in electric potential across membrane
C. Calculating Membrane Potentials from Ion Gradients
1. Nernst Equation
a. Ex = RT/zF ln([X]outside/[X]inside)
b. definitions:
(1) Ex = equilibrium membrane potential
(a) system must be at equilibrium
(b) membrane is permeable only to "X"
(2) R = gas constant = 1.987 cal/mol K
(3) T = temp in Kelvin degrees
(4) z = charge of the ion
(5) F = Faradays constant = 23,062 cal/mol V
(5) [X]outside = molar concentration of
"X" outside membrane
(6) [X]inside = molar concentration of
"X" inside membrane
c. holds for a simple system with only one ion "X"
d. used to APPROXIMATE what occurs in cells
-why "approximate"?
-is the cell PM permeable to only one ion?
-are the ion concentrations at equilibrium?
2. All ionic species affect membrane potentials
a. major ions account for MOST of the membrane potential
b. in cell, major ions are:
(1) Na+
(2) K+
(3) Cl-
(4) macromolecular anions
-proteins
-DNA
-RNA
c. ion species are unequally distributed
(1) Na+ mostly out
-tends to leak into cells
reducing membrane potential
-pumped back out by NaK pump
(2) K+ mostly in
-tends to leak out of cells
-helps produce membrane potential
-pumped back in by NaK pump
(3) Cl- mostly out
-concentration gradient drives Cl - in
-but repelled by membrane potential
(4) macromolecular anions mostly in
2. Goldman Equation accounts for all ion species
a. ions moving back and forth across membrane
-each ion species moves at its own rate
-rates of movement of each species
influence the membrane potential
b. continuous flux
c. need to consider steady state ion movements
d. see Goldman Equation
-each ionic species considered
- "P terms" are the relative permeabilities
-relative permeabilities obviates
need for absolute permeabilities
that are hard to measure
-eg: for squid axons
-if the rate of K+ permeability
is the standard => P = 1.0
-then, Na+ is 4% of K+ => P = 0.04
-then, Cl- is 45% of K+ => P = 0.45
III Electrical Excitability
A Features of excitable cells
1. have special ion channels
a. voltage-gated ion channels
(1) Na+ and K+ channels open
in response to changes in
membrane potential
(2) respond to membrane depolarization
with an action potential
b. ligand-gated ion channels
(1) open when the appropriate ligand
binds to the channel
B Patch Clamping
1. can record ion currents moving
through individual ion channels
2. equipment needed
a. fire polished glass micropipette
with tip diameter = 1 um
b. very sensitive electronic feedback
circuit called a voltage "clamp"
3. procedure:
a. place micropipette against cell's
plasma membrane
b. apply gentle suction so that
tight seal forms
c. "patch" of membrane should be small enough
so that it only contains 1 or a few channels
d. ionic current can enter or leave the
pipette only by passing through
the channel
e. researcher can measure flow of ions
through channel after changing the
polarizing voltage
C. Patch Clamp Findings
1. when open, Na+ channels always
conduct the same ion current
a. same number of ions per unit time
b. no partially open states
-either fully open or fully closed
2. channels can be characterized in terms
of their conductance
a. eg: voltage gated Na+ channels
-if a 50 mV potential is applied
-then 1 pA of current flows through
each channel = 6 million Na+ ions
per second
3. open channels conduct ions and
then become inactive
4. inactive channels must experience a
more negative potential before they can reopen
D. Voltage Gated Channels
1. multimeric channels
a. eg: K+ channels have 4 subunits
b. several separate protein subunits
comprise a functional channel
c. see a BACTERIAL K+ channel
with 3 bound K+ ions
d. see how the BACTERIAL K+ channel
resides in the membrane
2. monomeric channels
a. eg: Na+ channels have 1 subunit
with 4 separate domains
b. each of four domains is analogous
to the four separate subunits of the
multimeric channel
c. each domain has six transmembrane spans
d. span 4 has a positively charged amino
acid residues in the middle of its transmembrane span
-genetic engineering allows substitution of these
amino acids with neutral amino acid residues
-results in channels that don't open
- suggests that span 4 is part of
the voltage sensor
- mechanism is unknown
3. channel selectivity
a. ions must have right charge
b. ions must have right size
c. size of central pore
d. size of the hydrated ion
-see Table of Hydration Numbers and Radii
-compare Na+ and K+
e. ions passing through channel are stripped
of most hydrating water molecules
-see the O of one H2O in a K+ channel
-other H2O's have been stripped away
E. The Action Potential
1. coordinated opening/closing of ion channels
leads to the action potential
2. 1930's--discovery of giant axons in squid
a. these axons stimulate the explosive expulsion of
water from mantle cavity in squid
b. axon diameter = 0.5 to 1.0 mm
c. allows easy insertion of microelectrodes
-see cartoon of
measuring membrane potential
d. ALSO allows insertion of a 2nd electrode
-2nd electrode allows the researcher
to suddenly change the membrane
potential locally
-researcher can "trigger" what happens
-can make membrane potential more
positive => depolarize membrane
-eg: go from -60 mV to -40 mV
-can make membrane potential more
negative => hyperpolarize membrane
-eg: go from -60 mV to -80 mV
-usually researchers depolarize the membrane
-after a small depolarization (less than 20 mV)
the membrane potential just returns to resting
state at about -60 mV
-if a depolarization is large enough to reach a
threshold potential, an action potential begins
3. Action Potential = brief but large electrical depolarization AND
repolarization of neuron membrane that
proceeds down an axon in a wave
a. measured with apparatus above
-see a graphic action potential
b. action potential caused by:
(1) sudden inward movement of Na+ ions
-Na+ channels open fast
-Na+ follows its concentration gradient
-Na+ attracted to inside negative
membrane potential
(2) subsequent outward movement K+ ions
-K+ channels open more slowly
-K+ movement lags
-Na+ ions have dissipated the potential that
once kept K+ in
-now K+ free to leave cell
(3) after channels close, Na/K pump restores
the Na out & K in concentration gradient
c. once an action potential is initiated in one region of
a neuron, the depolarization "wave" will spread out
sequentially to the rest of the neuron = propagation
(1) see a simplified animation of an action potential
propagation
4. Phases of the Action Potential
a. resting phase
(1) membrane potential poised
at -60 mV inside negative
(2) voltage dependent Na+ and
K+ channels closed
(3) K+ channels 100x more leaky
than Na+ channels in resting phase
(4) the negative membrane potential helps
keep K+ ions in the cell even though there is
a large concentration gradient and
a leaky K+ channel
(5) subthreshold depolarization
-small depolarizations (less than 20 mV)
-only a few Na+ channels open
-Na+ comes in the open channels
-incoming Na+ further reduces the
membrane potential
-reduction in membrane potential leads
to more open Na+ channels
-chain reaction starts
-without the K+ channels, this would lead
to complete depolarization
-BUT, with subthreshold depolarizations the Na+
influx starts slowly
-recall: only "a few Na+ channels open"
-recall: "incoming Na+ further reduces the
membrane potential"
-recall: K+ more leaky than Na+
-recall: K+ leakage restrained by
membrane potential
-SO: K+ leaks out faster and prevents
further depolarization of membrane potential
(one Na+ in balanced by one K+ out = no net
change in potential)
-faster leakage is possible because
the restraint on K+ leakage is reduced by the inflowing Na+
-at -60 mV the K+ is held more tightly
-at -50 mV (some Na+ has rushed in) the K+
is not held as tightly and
more K+ leaks out down its large
concentration gradient
-at -40 mV (even more Na+ has rushed in) the
K+ is not held as tightly and even
more K+ leaks out down its large
concentration gradient
(eg: 400 mM inside vs 20 mM outside)
-SO: K+ leakage prevents the small
depolarizations from producing a
full scale chain reaction of Na+ channel opening
and the resulting action potential
(6) threshold depolarization
-occurs during depolarizing phase
b. depolarizing phase
(1) threshold depolarization
- larger depolarizations (greater than 20 mV)
cause many more Na+ channels to open
- flow of Na+ into the cell is faster than the
back leaking K+ can compensate for
- leads to greater depolarization
- get a full chain reaction
- leads to fully open Na+ channels
- Na+ rushes in until [Na+]in = [Na+]out
- leads to the peak (+40 mV) of the action potential
(2) see the ion fluxes
c. repolarizing phase
(1) once Na+ channels have let the
Na+ pass, the channels close and become inactive
(2) Na+ channels remain closed and inactive until
membrane potential becomes negative
(3) K+ channels open and K+ rushes out
(4) as K+ rushes out, the membrane potential repolarizes
-when there is one Na+ in for one K+ out then the
membrane potential will be back at -60 mV
d. hyperpolarizing phase
(1) because the K+ channels are wide open,
the repolarization OVERSHOOTS the
resting potential point
(2) as the membrane potential reaches the
resting potential, the K+ channels close
(3) now both Na+ and K+ channels are closed
(4) Na+ & K+ leakage continues
- K+ leaking 100X faster than Na+
(5) Na/K pump keeps pumping out 3 Na+ and in 2 K+
(6) membrane potential returns to resting potential at -60 mV
e. refractory phase
(1) after an action potential the neuron is inactive
(2) period of inactivity lasts a few milliseconds
(3) cell can't be triggered
(4) Na+ channels are closed AND inactive
-depolarization during refractory period
DOES NOT trigger channel opening
5. action potential propagation
a. two types of depolarizations
(1) passive spread of depolarization
-occurs in the dendrites and cell body
-dendrites and cell body have different kinds of
channels depending on nerve cell type
-ligand gated channels (synapses)
-gap junctions
-temperature gated channels
-mechano gated channels
-BUT VERY FEW voltage gated channels
-depolarization starts when one of various channels opens
-Na+ rushes in and depolarization occurs locally
-local depolarization allows K+ to diffuse toward
regions of more negative membrane potential
at the cell body
-the [K+] is much greater locally than the [Na+]
-wave of K+ mediated depolarization WEAKENS as
the wave spreads out from site of stimulous
-passive depolarizations can't
travel long distances
-starting an action potential usually requires
multiple simultaneous incoming signals
such that the passive depolarization gets
large enough to trigger an action potential
at the axon hillock
-passive depolarization reaches the
axon hillock
-voltage gated channels (Na+ and K+) are found
primarily at the axon hillock and the axon
- many Na+ channels are concentrated at
the axon hillock
-IF LARGE ENOUGH the passive depolarization
triggers the voltage gated channels to open
-many hillock channels => rapid and large depolarization
-depolarization spreads down axon
-as long as the passive depolarization remains
above the threshold level the axon hillock will
keep sending periodic action potentials down the axon
(2) action potential propagation (nonmyelinated)
-see Fig 9-17
-axon polarized with a resting potential
-inside 60 mV negative
-axon has a long string of channels
-consider four points (P, Q, R & S) along axon
-action potential is stimulated at P
-Na+ rushes in and an inside
positive potential develops
-Na+ ions move toward closest region
with negative potential
-this is the immediately adjacent area
that has not been depolarized
-as Na+ ions move, adjacent areas become
depolarized
-when Q is depolarized to its threshold level
the action potential starts at Q
-meanwhile, P starts to recover
-K+ ions flow out
-resting potential returns
-action potential at Q stimulates
depolarization at R
-can't go back to P because
Na+ channels still in refractory phase
-Q recovers, and R stimulates
action potential at S
(3) rate of action potential propagation
(a) how fast does the action potential
move down the axon?
(b) depends on electrical properties
of axon and cytoplasm
- cytoplasmic electrical resistance
to current flow
- how easily do ions move laterally
in cytosol?
- large neurons (eg: squid) have low
resistance => ion currents fast => impulses
go fast
- small neurons have higher resistance
=> ion currents slower => impulses slower
-capacitance of plasma membrane
-as the resting potential develops,
positive ions accumulate on the
outside of membrane and negative ions
accumulate on inside
- due to electrostatic attraction
- get locally higher [ion]
- get electrostatic attraction
- both conditions FAVORING rapid
movement of ions when channels open
-capacitance is related to the numbers of
positive charged and negatively charged
ions
-greater the capacitance, the slower the
impulse
-more negative charges inside PM
mean that more Na+ ions must come
in to neutralize the negative charges
and reduce the membrane potential
-more Na+ movement takes longer,
slows spread of depolarization
(4) myelin sheath
(a) supporting cells wrap layers of their own
PM around the axon
(b) each supporting cell surrounds about
1 mm of axon
-many cells required to cover whole axon
(c) sheath forms an insulating layer
(d) myelination DECREASES capacitance
- number on ions between axon and
supporting cells is controlled
(e) impulses can move faster
F. Synaptic Transmission
1. two types of synapses
a. electrical synapse between two neurons
(1) presynaptic neuron
(2) postsynaptic neuron
(3) presynaptic neuron connected to
dendrites of postsynaptic neuron
by gap junctions
(4) gap junctions allow ions to move
back and forth, another view
-depolorization spreads from one
cell to next by ion flow the gap junctions
b. chemical synapse
(1) presynaptic and postsynaptic neurons
are close but not connected
(2) gap about 20-50 nm wide
(3) arrival of action potential triggers
release of neurotransmitter molecules
into the gap between neurons
(a) neurotransmitters stored in
synaptic vesicles just under
PM of neuron
(b) an action potential allows
Ca+2 channels to open
-Ca+2 channels are found
only at the very ends of the axons
(c) Ca+2 rushes in
(d) increased [Ca+2] allows
synaptic vesicles to fuse with
PM and dump contents
(neurotransmitters) outside of
cell and into the gap
(4) neurotransmitters diffuse across gap
(5) neurotransmitters are bound by
postsynaptic neuron receptors
(a) eg: acetylcholine receptor = a ligand
gated Na+ channel
(b) two molecules of acetylcholine bind
to receptor and channel opens
-Na+ rushes in
(c) open channels lead to depolarization of
postsynaptic neuron
(d) action potential continues on in post
synaptic neuron
(6) properties of the acetylcholine receptor
(a) MW 300,000 daltons
(b) 4 different kinds of subunits
- alpha, beta, gamma, delta
- alpha binds aceylcholine
(c) active receptor has 5 subunits
- two alphas and one each of the rest
.
Ion Concentrations in Mammalian Cells and Blood Serum
| Ion | Cytoplasm (mM) | Blood Serum (mM) |
| K+ | 140 | 4 |
| Na+ | 12 | 145 |
| Cl- | 4 | 116 |
| HCO3- | 12 | 29 |
| protein neg charges | 138 | 9 |
| Mg+2 | 0.8 | 1.5 |
| Ca+2 | <0.0002 | 1.8 |
Back to the outline
.
Ion Concentrations in Squid Axons and Mammalian Neurons
| Squid Axons | Squid Axons | Mammalian Neuron | Mammalian Neuron |
| Ion | Outside (mM) | Inside (mM) | Outside (mM) | Inside (mM) |
| Na+ | 440 | 50 | 145 | 10 |
| Cl- | 560 | 50 | 125 | 10 |
| K+ | 20 | 400 | 5 | 140 |
Back to the outline
.
Hydration Numbers & Hydrated Radii of Ions
| Ion | Hydration Number | Hydrated Radius |
| Cs+ | 6 | 228 |
| K+ | 7 | 232 |
| Na+ | 13 | 276 |
| Li+ | 22 | 340 |
| Ba+2 | 28 | |
| Sr+2 | 29 | |
| Ca+2 | 29 | |
| Mg+2 | 36 | |
| Cd+2 | 39 | |
| Zn+2 | 44 | |
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