Signal Transduction Mechanisms:

Electrical Signals in Nerve Cells

Most animals have nervous system that : 1) collects

information, 2) processes information and 3) elicits

responses to the information.

Neurons are specially adapted for the transmission of

electrical signals.

o The cell body bears the nucleus and organelles.

o The dendrites receive (and combine) signals.

o The axons conduct signals.

o The myelin sheath surrounds the axon in a

discontinuous manner (form the nodes of Ranvier).

Nerve cells can be long (e.g., a motor neuron's cell body

in the spinal cord and the axon ends in your toes).

An axon ends with terminal bulbs or synaptic knobs that

transmit the signal through a specialized junction: the

synapse.

Every cell in the body is electrically active: to a

greater or lesser degree, they all pump ions

across the cell membranes to maintain

an electrical potential difference across the

membrane.

This difference in electrical charge between the

inside and outside of the membrane is the basis

for many types of physiological processes,

including transport of particles across the

membrane and signalling among cells.

In some cells up to 40% of energy is used to

power active transport, a process that

maintains or restores membrane potentials.

Membrane Potential and Action Potential

Membrane potential is a property of all cells and

reflects a difference in charge on either side of the cell

membrane. Normally, cells are net negative inside the

cell which results in the resting membrane potential or

Vm (a negative resting membrane potential).

The resting membrane potential depends on differing

concentrations of ions inside (cytoplasm) and

outside the membrane (extracellular fluid).

Large negatively charged molecules (proteins, RNA)

do not pass through the membrane to set up the

negative resting membrane potential.

If the cell membranes were simply permeable to these ions,

they would approach an equilibrium with equal concentrations

on each side of the membrane, and no voltage difference. But

there is a voltage difference, so the processes which produce

the membrane potential are not simply diffusion and osmosis.

Electrical excitability depends upon “ion channels” acting like

gates for the movement of ions through the membrane to

produce an action potential.

In passive channels, ions may freely move diffusively through

the channel. Leakage channels are the simplest type, since

their permeability is more or less constant.

Chemically gated channels pump Na+ (and some Ca+2) out of

the cell, while pumping in K+ in the ratio of 2 K+ for every 3 Na+

pumped out.

The flow of oppositely charged ions towards each other is the

potential or voltage. When the ions move, this is current.

Eventually electrochemical equilibrium (chemical versus

electrical) is established and the equilibrium membrane

potential is reached.

Sodium-Potassium Pump

Nerve, muscles and some glands share electrical

excitability which, in response to stimuli, causes

rapid changes in membrane potential (action

potential) to occur.

Within a millisecond, the membrane potential

changes from negative to positive and back.

In neurons, the action potential moves down the axon

as a nerve impulse.

Steady-state movement

of ions define the

membrane potential and

is maintained by the Na+-

K+ pump.

In the resting state of a

neuron, the inside of the

nerve cell membrane is

negative with respect to

the outside. The voltage arises from differences in concentration of the K+ and Na+ ions.

Depolarization (or a

lowering of the

membrane potential)

results from flow of

positive sodium ions into

the cell.

In nerve cells, a neurotransmitter can affect the activity of

a postsynaptic cell via 2 different types of receptor proteins:

ionitropic or ligand-gated ion channels, and metabotropic receptors.

1. Ligand-gated ion channels combine receptor and channel

functions in a single protein complex.

2. Metabotropic receptors usually activate G-proteins, which

modulate ion channels directly or indirectly through intracellular

effector enzymes and 2nd messengers.

Voltage-gated ion channels respond to differences in

voltage across the membrane (ligand-gated ion channels

respond to ligands).

Specific domains of voltage-gated channels act as

sensors and inactivators.

A specific transmembrane stretch of amino acids act as

voltage sensor.

Based upon the conformation of the voltage-gated

sodium channel, the channel can be closed but sensitive

to a depolarizing signal (channel gating) or completely

desensitized to the signal (channel inactivation) by the

inactivating particle, a stopper-like part of the channel

protein itself.

Recovery from an action potential is partly dependent on

a type of voltage-gated K+ channel which is closed at the

resting voltage level but opens as a consequence of the

large voltage change produced during the action

potential.

Voltage-gated Ion

Channels

The resting

potential of a

neuron is -70 to -80

mV.

Action potentials

propagate electrical

signals along an

axon. Initially, a

resting neuron is

made ready for

electrical activity

through the balance

of ion gradients and

membrane

permeabilities.

A small amount of

depolarization

(<+20mV) will

normally result in

recovery without

effect.

More depolarization causes the membrane to

reach the threshold potential at which the nerve

cell membrane rapidly changes electrical

properties and ion permeability to initiate an

action potential.

The action potential is a brief depolarization/

repolarization that propagates from the site of

origin.

Graded Potentials Graded potentials

are short lived

depolarizations or

hyperpolarizations

of an area of

membrane.

These changes

cause local flows of

current that

decrease with

distance.

The more intense the stimulus, the more ion channels that are opened, and the greater the voltage change.

The action potential results from the rapid

movement of ions through axonal membrane

channels and the increased sodium current results

in a positive feedback loop known as the Hodgkin

cycle.

Sub-threshold depolarization results in no action

potential generated, which is at least partially due to

the outward movement of K+ ions. If the K+ ion exit

cannot compensate for the influx of Na+ ions, the

membrane reaches the threshold of depolarization.

When the voltage-dependent Na+ channels open, Na+

flows in during the depolarizing phase.

Once the membrane potential peaks, the

repolarizing phase begins with the inactivation of

the Na+ channels (blocking the Hodgkin cycle) and

the opening of the voltage-gated K+ channels.

The recovery is due to the passive movement of

ions- not the action of the Na+/K+ pumps.

During the absolute refractory period (~few

milliseconds), Na+ channels cannot be opened by

depolarization and no action potential can be

generated.

During the hyperpolarizing phase, the Na+channels

are reactivated but Na+ flow is opposed by K+

currents which produces a relative refractory

period.

1.The passive spread of

depolarization causes

cations (mostly K+) to

spread to adjacent

regions of the axon's

cytoplasm.

2.As the depolarization

spreads, it loses its

magnitude and MUST

be actively propagated

to move far.

3.Propagation depends

upon the passive

spread of depolariza-

tion to induce the

membrane potential in

adjacent parts of the

axon to reach the

threshold potential

which then triggers the

intake of Na+ ions and

continuation of the

cycle.

Action potentials are propagated

along the axon without losing

strength by active propagation:

4.At the axon hillock, a

great influx of Na+

ions can occur which

specify that action

potentials initiated

here are propagated

down the axon. The

propagated action

potential is the nerve

impulse.

5.The rate of impulse

transmission depends

on electrical

properties of the

axon such as the

electrical resistance

of the cytosol and the

ability to retain

electric charge

(capacitance) of the

plasma membrane.

For example, signals move from the dendrites

through the cell body to the base of the axon

(the axon hillock) where Na+ channels are

concentrated.

The hyperpolarizing phase results from the

increased permeability of K+ due to the open

voltage-gated K+ channels. The membrane

potential returns to resting state with the closing

of the voltage-gated K+ channels.

Hyperpolarization prevents the neuron from

receiving another stimulus during this time, or at

least raises the threshold for any new stimulus.

Hyperpolarization also prevents any stimulus

already sent up an axon from triggering another

action potential in the opposite direction. It

assures that the signal is proceeding in one

direction.

After hyperpolarization, the Na+/K+ pump

eventually brings the membrane back to its

resting state of -70 mV .

The discontinuous myelin

sheath acts like an electrical

insulator surrounding the axon.

The neurons of the CNS have

myelin sheath composed of

oligodendrocytes and in the

PNS the myelin sheath is

composed of Schwann cells. In

each case, the myelin cells

wrap several layers of their

plasma membranes around the

axon.

Each Schwann cell surrounds a

stretch of 1 mm of axon, with

many Schwann cells acting to

insulate each axon.

Myelination permits a

depolarization of events to

spread farther and faster

than without because of

saltatory propagation.

This process depends

upon the gathering of

voltage-gated sodium

channels at the nodes of

Ranvier.

Action potentials jump

from node to node

(saltatory propagation)

which is very rapid when

compared to propagation

in neurons that have the

myelin removed.

SYNAPSE

Synapses are specialized junctions through which

NS cells signal to one another and to effectors

(muscles or glands). They provide the means through

which the NS connects to and controls the other

systems of the body.

Nerve cells communicate with muscles, glands

and other nerve cells via synaptic

transmission. In an electrical synapse, the axon

of the presynaptic neuron connects to the

dendrite of postsynaptic neuron by gap

junctions.

In a chemical synapse, the presynaptic

and postsynaptic neurons are

separated by a gap, the synaptic cleft.

A NEUROTRANSMITTER is a small molecule that, through

the interaction with a specific receptor, relays a signal

across nerve synapses. Neurotransmitter molecules that

are kept in the terminal bulbs or synaptic knobs are

secreted into the synaptic cleft and then bind to receptors

in the postsynaptic neuron. This generates an electrical

signal to stimulate or inhibit a new action potential.

A neurotransmitter must: 1) cause a response

when injected into the synaptic cleft, 2) occur naturally

in the presynaptic neurons and 3) be released when the

presynaptic neurons are stimulated.

An

excitatory

neuro-

transmitter

causes

depolari-

zation

An

inhibitory

neuro-

transmitter

causes

hyperpola-

rization in

the post-

synaptic

neuron.

Neurons can integrate both excitatory and inhibitory

signals from other neurons.

The summation of synaptic inputs leads to whether

or not an action potential is formed in the

postsynaptic neuron.

Acetylcholine is the most common neurotransmitter in

vertebrate outside of the CNS to form cholinergic synapses

between PNS neurons and at neuromuscular junctions.

The catecholamines (dopamine, norepinephrine, epinephrine: all

tyrosine derivatives) are found in adrenergic synapses at

junctions between nerves and smooth muscles and nerve-nerve

junctions in the brain.

Other neurotransmitters are other amino acids and

derivatives (histamine, serotonin, gamma-aminobutyric acid

[GABA], glycine, glutamate). Serotonin functions as an

excitatory neurotransmitter in the CNS by indirectly closing the

K+ channels.

The neuropeptides are short chains of amino acids formed by

cleavage of precursor proteins and stored in secretory vesicles.

The enkephalins are neuropeptides that are produced in the

brain to inhibit pain reception.

The neuropeptide endocrine hormones (prolactin, growth

hormones and leutinizing hormone) act on tissues other than the

brain.

Elevated calcium levels stimulate

secretion of neurotransmitters from

the presynaptic neurons.

The neurotransmitters are stored in

neurosecretory vesicles in the

terminal bulbs.

The release of calcium within the

terminal bulb mobilizes

neurosecretory vesicles rapidly (by

the phosphorylation of synapsin and

release from the cytoskeleton) and

causes the fusion of the vesicles to

the plasma membrane and

neurotransmitters release.

Exocytosis of neurotransmitters

requires the docking and fusion of

vesicles with the plasma membrane

requires ATP and voltage-gated

calcium channels.

When the action potential

reaches the ends of the

axon, voltage-gated calcium

channels open and calcium

flood in.

This initiates the docking of

the vesicles at the

presynaptic neuron's

membrane in an active zone

through the action of

docking proteins

(synaptotagamin,

synaptobrevin, syntaxin).

The docking process is

blocked by neurotoxins such

as tetanus toxin (in the spinal

cord) and botulinum toxin (in

the motor neurons).

Neurotransmitters are detected by specific receptors on

postsynatic neurons such as ligand-gated

channels.The acetylcholine receptor is a ligand-gated

sodium channel that binds two molecules of acetylcholine

to open. This receptor is specifically bound by snake venom

components (alpha-bungarotoxin and cobratoxin).

The GABA (gamma-aminobutyric acid) receptor is a

ligand-gated Cl- channel which produces an influx of Cl-

ions in the postsynaptic neuron.

The entry of Cl- ions neutralize the effect of Na+ influx

on the membrane potential which reduces

depolarization and may prevent initiation of an action

potential in the postsynaptic neuron.

Benzodiazeprine drugs (Valium and Librium) enhance

the effects of GABA on the receptor to produce a

tranquilizing effect.

For neurotransmitters to work effectively and not

overstimulate or inhibit, they must be neutralized shortly

after their release by either degradation or recovery by

the presynaptic neuron.

Acetylcholine is hydrolyzed by acetylcholinesterase.

Some neurotransmitters are returned to the presynaptic

axon terminal bulbs by specific transporter proteins

(endocytosis).

Brain images showing decreased dopamine (D2) receptors in the brain

of a person addicted to cocaine versus a nondrug user. The dopamine

system is important for conditioning and motivation, and alterations such

as this are likely responsible, in part, for the diminished sensitivity to

natural rewards that develops with addiction.

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aps.org/education/itip/im

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ki/Membrane_potential