Signal Transduction Mechanisms: I. Electrical Signals in Nerve Cells

The Nervous System

The nervous system has two main cell types neurons and glial cells
1) sensory neurons act to detect stimuli (photoreceptors, olfactory, touch)
2) motor neurons transmit signals from CNS to muscles (and glands)
3) interneurons process signals from other neurons.

The glial cells are...
Microglia are phagocytes that fight infection.
Oligodendrites and Schwann cells form the insulating myelin sheath around the neurons.
Astrocytes form blood-brain barrier.

Neurons have a variety of shapes such as
    a) pyramidal (cerebral cortex),
    b) short-axon cells (also cerebral cortex),
    c) Purkinje cell (cerebellum),
    d) axonless horizontal cell (retina:eye)

Neurons are specially adapted for the transmission of electrical signals.
The cell body bears the nucleus and organelles.
The dendrites receive (and combine) signals.
The axons conduct signals.
The myelin sheath surrounds the axon in a discontinuous manner (form the nodes of Ranvier).
Nerve cells can be long (for example:  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.

Membrane Potential and Action Potential

The resting membrane potential depends on differing concentrations of ions inside (cytoplasm) and outside the neuron (extracellular fluid).
Large negatively charged molecules (proteins, RNA) do not pass through the membrane to set up the negative resting membrane potential.
The cytosol is high in potassium due to the sodium-potassium pump.
The outward transport of sodium ions is coupled to the inward transport of potassium ions against their electrochemical gradients.
The potassium ion gradient drives potassium out of the cell.
The electroneutrality of the cytosol requires potassium to be the counterion for the large negatively charged molecules.
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.

Ions trapped inside the cell have important effects on resting membrane potential.
The high sodium concentration outside the cell membrane balances the osmolarity of the cytosol.
The membrane is only poorly permeable to sodium and the sodium/potassium pump transport sodium back out and potassium back into the cell through ATP hydrolysis.
Steady-State concentrations of common ions affect resting membrane potential.
Depolarization (or a lowering of the membrane potential) results from flow of positive sodium ions into the cell.
Steady-state movement of ions define the membrane potential and is maintained by the sodium/potassium pump.

Technique:
Patch clamping (single-channel recording) and various molecular biological techniques allow the activity of single ion channels to be monitored.

Electrical excitability in excitable cells depends upon ion channels to act like gates for the movement of ions through the membrane to produce an action potential.
Ion channels are ion-conducting pore-forming integral membrane proteins.
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.

Action Potential

Action potentials involve rapid changes in the membrane potential of the axon.
Action potential can be measured in large axons (such as squid giant axons) by inserting a stimulating electrode and measuring the membrane potential changes with a second, recording electrode.
A brief stimulation by a pulse of 20 mV (~-60 mV to ~-40 mV) will surpass the threshold potential and trigger an action potential.
The membrane potential rapidly (<1 ms) changes to about +40 mV.
Then hyperpolarization occurs and the membrane potential drops to -75 mV before restabilizing at -60 mV.

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.
Subthreshold depolarization results in no action potential generated, which is at least partially due to the outward movement of potassium ions.
If the potassium ion exit cannot compensate for the influx of sodium ions, the membrane reaches the threshold of depolarization.
When the voltage-dependent sodium channels open, sodium flows in during the depolarizing phase.
Once the membrane potential peaks, the repolarizing phase begins with the inactivation of the sodium channels (blocking the Hodgkin cycle) and the opening of the voltage-gated potassium channels.
The hyperpolarizing phase results from the increase permeability of potassium due to the open voltage-gated potassium channels.
The membrane potential returns to resting sate with the closing of the voltage-gated potassium channels.
The recovery is due to the passive movement of ions not the action of the sodium/potassium pumps.
During the absolute refractory period (~few milliseconds), sodium channels cannot be opened by depolarization and no action potential can be generated.
During the hyperpolarizing phase, the sodium channels are reactivated but sodium flow is opposed by potassium currents which produces a relative refractory period.

Action potentials are propagated along the axon without losing strength by active propagation as follows:
The passive spread of depolarization causes cations (mostly potassium) to spread to adjacent regions of the axon's cytoplasm.
As the depolarization spreads, it loses its magnitude and MUST be actively generated (propagated) to move far.
Propagation depends upon the passive spread of depolarization to induce the membrane potential in adjacent parts of the axon to reach the threshold potential which then triggers the intake of sodium ions and continuation of the cycle.
For example, signals move from the dendrites through the cell body to the base of the axon (the axon hillock) where sodium channels are concentrated.
At the axon hillock, a great influx of sodium ions can occur which specify that action potentials initiated here are propagated down the axon.
The propagated action potential is the nerve impulse.
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.

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.

Neurotransmitters

A neurotransmitter is a small molecule that, through the interaction with a specific receptor (a key and lock mechanism), relays a signal across nerve synapses.
An excitatory neurotransmitter causes depolarization and an inhibitory neurotransmitter causes hyperpolarization in the postsynaptic neuron.
A neurotransmitter must…
1) cause a response when  injected into the synaptic cleft,
2) occurs naturally in the presynaptic neurons and
3) be released when the presynaptic neurons are stimulated.

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 potassium 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 specific receptors on postsynatic neurons such as ligand-gated channels.
1) The acetylcholine receptor is a ligand-gated sodium channel that binds two molecules of acetylcholine to open.
The acetylcholine receptor is specifically bound by snake venon components (alpha-bungarotoxin and cobratoxin).
2) The GABA  (gamma-aminobutyric acid) receptor is a ligand-gated chloride channel which produces an influx of chloride ions in the postsynaptic neuron.
The entry of chloride ions neutralize the effect of sodium 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).

Nerve signals are processed and integrated through the accounting of small changes in membrane potential caused by the binding of neurotransmitters to the receptors.
Postsynaptic potentials (PSPs)  can be excitatory (EPSP) or inhibitory (IPSP).
The EPSP must build up in the postsynaptic neuron to the threshold level to allow the formation of an action potential.
Neurons can integrate signals from other neurons
1) through temporal summation (where a number of EPSPs occur quickly without enough recovery time between the EPSPs to cause a depolarization event) or
2) through spatial summation (a number synaptic inputs combine to cause a depolarization event).
Neurons can integrate both excitatory and inhibitory signals from other neurons.
Thus the summation of synptic inputs leads to whether or not an action potential is formed in the postsynaptic neuron.