Concepts of Biology (BIOL116) - Dr. S.G. Saupe; Biology Department, College of St. Benedict/St. John's University, Collegeville, MN 56321; ssaupe@csbsju.edu; http://www.employees.csbsju.edu/ssaupe/

Nervous System: Neurons

I. Cell Types

A. Neurons - conduct nerve impulses

• dendrites – short, highly branched, receive signal and carry it toward cell body
• axons – long, carry signal away from cell body; terminal branches
• cell body – large section, contains the nucleus and other goodies
• myelin – lipid coating derived from membrane of Schwann cells; acts as a kind of insulation
• Nodes of Ranvier – gaps between Schwann cell
• synaptic terminal – end of the axon, junction with another neuron or effector
• neuron form/function related - see diagram/overhead of different neurons

B. Supporting, or glial, cells.
    The function of these cells is to structurally reinforce, protect, insulate or otherwise assist the neurons.  Nervous system  housekeeper cells. There are lots of glial cells; in fact, in the brain there are 10-50x more glial cells than neurons. Glial cells include:

1. Astrocytes (star-shaped; they have many functions including - line capillaries, part of the blood brain barrier which serves to keep toxins from the brain, phagocytosis)
2. Microglia - phagocytic cells, remove cellular debris
3. Oligodendrocytes (wrap and insulate nerves). 
4. Schwann cells – wrap around neuron like a "jelly roll".  Have a myelin (fatty substance) sheath which is like insulation on a wire.  Vertebrates;  outside CNS in peripheral nervous system

C.  Construction.
    Neurons are bundled together to form nerves.  Ganglia - clumps of cell bodies

II. Membrane Potentials

A. Charge distribution.
    At rest, neurons (and most other cells, too) exhibit an electrical charge difference across the membrane. This difference, or membrane potential, can be measured with tiny electrodes connected to a voltmeter or an oscilloscope. At rest, the membrane potential is -60 millivolts (mV), which means that the inside of the cell is negative in comparison to the outside. This is ultimately due to an unequal distribution of ions, especially sodium and potassium, between the outside and inside of the cell (see Table 1).

B. Nernst Equation.
    Relates the ion distribution to the membrane potential when the cell is at rest.  See equation in text.  Thus, if the ion distribution is know, the membrane potential can be calculated.  

C.  Why the unequal charge distribution? 
    The membrane is permeable to both potassium and sodium (recall that ions move through membranes slowly).  These ions diffuse through protein channels in the membrane.  There are separate "leakage channels" for both potassium and sodium and they are always "open", thereby permitting the diffusion of sodium and potassium down their concentration gradient.  Thus, potassium diffuses from inside to outside and sodium diffuses from outside to inside. 

    The membrane is much more permeable to potassium so there is a net flux (leakage) of potassium, and hence positively-charged particles, out of the cell. This is the result of more potassium leakage channels and a steeper concentration gradient in potassium between inside and outside of the cell.  Since the cell is permeable to both sodium and potassium, over time, you would expect an equilibrium state would be reached at which point the concentration of sodium and potassium would be approximately equal inside and outside of the cell, and hence no membrane potential.

    So, what maintains the unequal charge distribution?  The sodium-potassium pump!  The pump is another integral protein complex that requires ATP and actively transports sodium out of the cell and potassium into the cell. For every three sodium that are moved out, two potassium are moved in.  Thus, the sodium-potassium pump maintains the ion gradient across the membrane.  It is an active (energy-requiring process) because it is moving the ions against their concentration gradient.

III. Excitability.
    Some cells are excitable, that is, they can change their membrane potential. This occurs when the membrane depolarizes (switches polarity - the inside becomes positive relative to the outside) or hyperpolarizes (becomes more negative inside relative to outside).  A nerve impulse is simply a reapid change (reversal) neuronal membrane permeability.

A. Special Ion Channels (Voltage-Gated Ion Channels; Voltage-Activated Ion Channels)
    In the membrane there are proteins that respond to changes in membrane potential/voltage.  In response, these gates permit the passage of sodium or potassium in/out of the cell.  Let's examine the voltage-activated gates of sodium and potassium.

Sodium Channel – this channel permits the diffusion of sodium. It has two gates: 

• Gate 1 (Activation Gate) - closed at rest; depolarization causes it to open rapidly
• Gate 2 (Inactivation Gate) - open at rest, depolarization causes it to close slowly. 
• At rest, sodium cannot pass through these gates because gate 1 is closed. 

Potassium Channel - this channel permits the diffusion of potassium 

• closed at rest
• depolarization causes it to open slowly.

B. Opening the gates.  Consider what happens when...

    1.  ...the potassium gate opens:

potassium gate open � potassium diffuses out � inside becomes more negatively charged, outside more positive � hyperpolarization (membrane potential becomes more negative).

    2.  ...the sodium activation gate opens:

sodium gate open � sodium diffuses in � cell interior becomes positive, outside more negative � depolarization. If the depolarization reaches ca. -50 to -55 mV it will trigger an action potential, which is an all-or-nothing response.

IV. Action potential
    A nerve impulse is rapid (lasts 1-2 msec) transient depolarization of the membrane. It sweeps down the neuron like a wave (at a rate of about 100 m sec^-1). 

A.  Phases.
    An action potential can be dissected into the following phases:

1. Resting phase.
           Membrane potential -60 mV; potassium gate closed; sodium gate 1 closed; sodium gate 2 open. No "excess" movement of sodium or potassium across membrane
   
   
2. Depolarization phase.
       Local depolarization of membrane occurs � membrane potential reaches threshold potential -55 mV) � acts on ion gates. Sodium gate 1 opens quickly  � rapid entry of sodium into cell � cell depolarizes. Sodium gate 2 begins to close; it is slow so has little immediate effect. The potassium gate begins to open, it is slow so has little immediate effect.
   
   
3. Repolarization phase.
       Sodium gate 2 now closed, prevents entry of additional sodium. Potassium gate now fully open, and allows loss of potassium. The net result is a loss of positive charge from inside the cell which causes the repolarization.
   
   
4. Undershoot.
       Excess potassium may leak out of the cell causing a hyperpolarization of the membrane.

B.  Refractory period.
    Time period following an action potential during which the cell gates are returning to their original positions. The cell cannot respond to another nerve impulse during this period.

C.  Nerve impulse.
    Wave of action potential spreads along the neuron. It doesn’t turn back on itself because of the refractory period.

D.  Rate of conduction.
    In unmyelinated nerves, speed is directly related to the diameter of the axon. Rates vary from about 1 – 10 m s^-1. Saltatory conduction occurs when action potentials jump between nodes of Ranvier. These occur much faster.  Voltage channels just in node area.

V. Communication between adjacent nerve cells.
    A few neurons are hard-wired (i.e., are directly connected to one another, as in gap junctions). These are called electrical synapses and important for really fast responses. However, most neurons are not in contact with one another, rather there is a gap (ca. 25 nm), called the synapse or synaptic cleft, between the adjacent cells. So, how does the nerve impulse get across the gap in these chemical synapses? Chemical signals = neurotransmitters.

Action potential arrives at synaptic terminal � stimulates voltage-gated calcium channels to open �  uptake of calcium � stimulates migration of vesicles containing neurotransmitter to the membrane surface � vesicles fuse with the membrane releasing their contents into the gap � diffuses across gap � binds to appropriate receptor � opens gates for sodium and potassium or stimulates a second messenger system that opens sodium and potassium gates � causes membrane depolarization (or hyperpolarization) � threshold potential � action potential.

A. Various neurotransmitters have been identified. 
    Many known. Acetylcholine is a common one involved in muscle contractions and other responses. Norepinephrine, serotonin, and dopamine are involved in mood, mental state, ADD, schizophrenia. Gamma-amino butyric acid (GABA) is in the spinal cord and brain.  The opiate types, endorphins and enkephalins are involved in pain perception.

B. Too much neurotransmitters is a bad thing. 
    In other words, the neurotransmitters must be removed after they do their job. Many are broken down by enzymes. For example, acetylcholinesterase breaks down acetylcholine. Others like serotonin are reabsorbed by the axon. Some drugs work by the inhibition of the reuptake of the neurotransmitter.  For example, cocaine prevents the reuptake of serotonin.

C.  Secondary messenger system.
    As mentioned, the action of the neurotransmitter may be mediated by a secondary messenger system.  In this case:  neurotransmitter � binds to the receptor protein � activates G proteins  � adenyl cyclase � converts ATP to cyclic AMP (cAMP) � activates kinases �  phosphorylates proteins  � closes potassium channel �  depolarization

VI.  Excitatory & Inhibitory Impulses
    Some neurons cause depolarization of membrane (i.e, motor neuron and skeletal muscle).  These are called excitatory.  Other neurons cause hyperpolarization (inhibitory).  GABA and glycine act in this manner.  Ultimately, the final response of a nerve is a sum of the excitatory and inhibitory responses received - typically at the axon hillock (at base of axon, not insulated by glial cells, many voltage gated channels) 

VII. Chemicals and Nerves
   These can exert their effect in a variety of places. For example, DDT interferes with the sodium/potassium pump; the anesthetics cocaine, lidocaine and procaine block sodium ion channels. Some poisons mimic the effect of the naturally-occurring neurotransmitter (i.e., hallucinogenic drugs, muscarine)

VII. Video - "The Neuron Suite" by James Burke. Available at Alcuin Library - QP 376.B8.

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