Membrane Potentials

As a result of the permeability properties of the plasma membrane, there is a separation of charges across membrane that results in a voltage difference between the inside and the outside of a cell.  This difference is referred to as the membrane potential (V_m).  It exists in all cells, but can only be changed in electrically excitable cells such as neurons and muscle.

Across the cell membrane there exists an unequal concentration of Na⁺ and K⁺  (diffusion or concentration gradient).

• Na⁺ is more concentrated outside the cell in the extracellular fluid.

• K⁺ is more concentrated inside the cell in the intracellular fluid.

There also exists an unequal distribution of charges across the cell membrane (electrical gradient).

• Inside is negatively charged relative to the outside of the cell due , in part, to the presence of "fixed" negatively charged ions (anions).

In an unstimulated state, the cell membrane is much more permeable to K⁺ than Na⁺. As a result, K⁺ accumulates within the cell due to its attraction to the fixed anions.  (Remember, unlike charges attract and like charges repel.)

The electrical properties of cells are based on the difference in concentrations of specific ions across the membrane and on the permeability of the cell membrane to each ion.

If K⁺ was the only diffusible ion, the rate of K⁺ entry (due to electrical attraction) would = the rate of K⁺ exit (due to diffusion) = equilibrium.

At equilibrium, inside of cell would be negative (approximately -90 mV) compared to the outside = K⁺ equilibrium potential (E_K).  A membrane potential of -90 mV would prevent the net diffusion of K⁺ out of or into the cell.  E_K is a theoretical membrane potential.

Can calculate equilibrium potential for single ions with the Nernst Equation =  E_x = 61/z log [X_o]/[X_i] at 37^oC.  "x" represents the ion for which the Nernst equation is being calculated, "z" is the valence (charge of the ion), X_o is the concentration of the ion outside the cell, and X_i is the concentration of the ion inside the cell.

Membrane potential in an unstimulated cell (one not producing impulses) is referred to as the resting membrane potential (V_rest).

Many ions contribute to V_rest, but K⁺ has the greatest effect.

V_rest is usually < E_K because some Na⁺ leaks into the cell due to attraction from the fixed anions.   

Why then does not more Na⁺ enter?  Membrane is not very permeable to Na⁺ in the resting state. 

Movement of ions to counter "leaks" requires constant correction by Na⁺/K⁺ pumps whereby the ions are moved against their concentration gradients by primary active transport (PAT).  PAT is an energy (ATP) requiring process in which 3 Na⁺ ions are pumped out of the cell for every 2 K⁺ ions pumped into the cell.

• Results in:

1. Relatively constant intracellular concentrations of Na⁺ and K⁺.

2. Relatively constant resting membrane potential (-65 to -85 mV) in nerves and muscles .

Neurons and Supporting Cells

Primary function of nervous system: Rapid control and communication within the body.

Divisions of Nervous System:

• Central Nervous System (CNS) - Brain and Spinal Cord

• Peripheral Nervous System (PNS) - Cranial and Spinal Nerves (outside of the CNS)

Components of Nervous System (NS):

• Neurons (20-25% of total nerve cells)

• Structural and functional units of NS.

• Specialized to respond to stimuli (chemical and physical), conduct action potentials, release chemical regulators.

• Neuroglial (glial) cells = Schwann cells, oligodendrocytes, etc; (75-80% of total nerve cells)

• Support neurons structurally and metabolically.
• Generally do not produce action potentials.
• Produce myelin sheath in the PNS (Schwann cells) and CNS (oligodendrocytes). Axons can be myelinated or unmyelinated. One oligodendrocyte forms myelin around several axons.
• Schwann cell membrane wraps around the axon several times like electrician's tape wraps around a wire. One Schwann cell forms myelin around one axon.

Anatomy of Neurons:

• Cell body (soma) - Contains the nucleus.

• Dendrites - Carry information into neuron, and extend from soma.

• Axon - Conducts action potentials (AP) away from soma.

• Axon hillock - Transition between soma and axon; region responsible for the initiation of the AP.

• Nodes of Ranvier - Areas of interruption of myelin sheath along axon.

• Myelin sheath - Surrounds and insulates axon.  Its presence increases rate of conduction along the axon.

• Axon terminal (bouton)- Transmits information chemically from neuron to neuron or neuron to muscle or gland.

All cells have a resting membrane potential, but only a few types of cells can alter their membrane potential in response to stimulation.

Neurons have 2 properties:

• Excitability (irritability) - Ability to respond to a stimulus.

• Conductivity - Ability to transmit an impulse.

Membrane potential vs. time diagram: See Figs. 7.11 and 7.13.

• Depolarization - Reversal of membrane polarity (charge) due to positive ions flowing into the cell. It is shown by an upward deflection on diagram.

• Hyperpolarization - Increase in the negativity of the inside of a cell membrane with respect to V_rest  as a result of the membrane becoming more negative (loss of positive ions from cell or addition of negative charges). It is shown by a downward deflection on the diagram.

• Repolarization - A return to the resting membrane potential after a depolarization.

Permeability of the axon to Na⁺ (and K⁺) is regulated by gates (proteins in membrane that open or close to affect the passage of ions) that are voltage-regulated.  In other words, they open in response to depolarization.

Some ion channels are not gated and are thus always open (leakage channels).  At rest, many K⁺  channels are always open .

At -70 mV (V_rest), membrane is relatively impermeable to Na⁺ and slightly permeable to K⁺.

When the membrane is depolarized to a threshold level, the Na⁺ gates open first. Eventually this will be followed by the opening of the K⁺ gates. While the K⁺ gates are opening the Na⁺ gates are inactivating.

• Threshold potential - Minimum membrane potential required to obtain a response (an action potential in this case).

Opening of voltage-regulated gates produces an action potential.

The opening of Na⁺ gates allows Na⁺ to diffuse into the axon, thus further depolarizing the membrane in a positive feedback fashion.

• Positive feedback - A response mechanism that results in the amplification of an initial change.

Depolarization   →   Na⁺ gates open   →   Na⁺ diffuses into cell   →   More depolarization

Inward diffusion of Na⁺ causes a reversal of membrane potential toward +66 mV = E_Na = Na⁺ equilibrium potential.  A membrane potential of +66 mV would prevent the diffusion of Na⁺ into the cell.

At the peak of the AP, open channels are inactivated and no longer respond to depolarization.

Opening of K⁺ gates and outward diffusion of K⁺ causes the reestablishment of the V_rest = repolarization.

• Action Potential (AP; nerve impulse) - Electrical event in which the charge of the membrane potential is rapidly reversed and reestablished.

Na⁺/K⁺ pumps will remove Na⁺ and recover K⁺ after the AP.

Characteristics of AP's:

They are all-or-none events as long as the membrane is depolarized to threshold.

They have constant duration and amplitude within each individual cell.

       - Code for stimulus strength in the nervous system is frequency modulated (FM), not amplitude-modulated (AM).  The process of recruitment of more axons can also code for stimulus strength.

They have refractory periods (which refers to the inability to respond to a stimulus) which prevent AP's from running together and ensures unidirectional propagation along the axon.

• Absolute refractory period - Period in which the axon cannot be stimulated to produce another AP.

• Relative refractory period - Period in which the axon can be stimulated to produce another AP, but only if a stronger stimulus is applied.

Conduction (Regeneration) of Action Potentials

• Occurs when one AP serves as the depolarizing stimulus for production of the next AP in the axon that contains voltage-regulated gates.

• In unmyelinated axons, AP's are produced in every patch of membrane that contains Na⁺ and K⁺ gates along the entire length of the axon. Therefore, the conduction rate is relatively slow.

• In myelinated axons, AP's are only produced at the nodes of Ranvier.  This results in the AP "jumping" from node to node = saltatory conduction.  Therefore, the conduction rate is relatively fast.

• Na⁺ gates are highly concentrated at the nodes and almost absent between the nodes = internodes.

Rates of conduction are significantly greater in myelinated axons (up to 120 m/sec) compared to unmyelinated axons (< 1 m/sec).

AP's are conducted along the axon without a decrease in amplitude (they are conducted without decrement).

Conduction rate can be increased by: 1) Myelination and 2) Increased axon diameter

• Synapse - Functional connection at which an impulse is transmitted from one cell to another. Second cell can be either another neuron, a muscle, or a gland.

• Presynaptic neuron - Releases neurotransmitter

• Postsynaptic neuron - Binds neurotransmitter

• Synaptic Cleft - Space between presynaptic and postsynaptic cells.

Classification of synapses:

• Axodendritic, axosomatic, axoaxonic

Types of synapses:

• Electrical

• Found within nervous system, smooth muscles, and cardiac muscle.

• Communication occurs via direct passage of electrical current through cell to cell connections (gap junctions).  Gap junctions contain proteins called connexins.

• Little to no synaptic delay because cells are in contact with one another.

• Conduction is two-way.

• Chemical

• Conduction is one-way .

• Has synaptic delay (0.5-1 msec) due to time required for the release and diffusion of neurotransmitter.

Characteristics of Transmission at Chemical Synapses Using Acetylcholine as an Example:

• AP in presynaptic cell

• Depolarization of the plasma membrane of the presynaptic axon terminal

• Entry of Ca²⁺ through voltage-regulated gates into presynaptic terminal which activates various proteins necessary for docking of vesicle

• Fusion of neurotransmitter (NT)-containing synaptic vesicles with plasma membrane and exocytosis of NT

• # of vesicles undergoing exocytosis is related to the frequency of AP's. Amount of NT in 1 vesicle = quanta.

• Ca²⁺ couples electrical excitation of axon to NT release.

• Diffusion of NT across the synaptic cleft

• Binding of NT to specific receptors on the plasma membrane of the postsynaptic cell

• Acetylcholine (ACh) binds, is released, and then inactivated by acetylcholinesterase (AChE).

• After NT binding, NT can either bind to another receptor, be inactivated by an enzyme, taken back up by the presynaptic terminal (reuptake), or diffuse away.

• Opening of chemically regulated gates on the postsynaptic membrane to specific ions

• Change in the membrane potential of the postsynaptic cell by simultaneous diffusion of Na⁺ and K⁺

Depolarizations in postsynaptic neurons produced by neurotransmitters released from presynaptic neurons are called excitatory postsynaptic potentials (EPSP's).

• Occur in cell bodies and dendrites.

• Decrease in amplitude as they are conducted.

• EPSP's are graded and capable of summation. This allows information from many neurons to be integrated together.

• EPSP's travel to axon hillock and, if of sufficient magnitude, will generate AP's.

Types of summation:

• Spatial summation - Addition of synaptic depolarizations when 2 or more separate inputs arrive simultaneously on a single postsynaptic neuron.

• Temporal summation - Addition of synaptic depolarizations when 2 or more postsynaptic potentials are elicited within a short time after the first because of successive waves of neurotransmitter release in the presynaptic neuron.

Hyperpolarizations in postsynaptic neurons produced by neurotransmitters released from presynaptic neurons are called inhibitory postsynaptic potentials (IPSP's).

• Result in postsynaptic inhibition.

• Drive the membrane further from threshold and, therefore, require stronger EPSP's to reach threshold and generate AP's.

Examples of neurotransmitters:

• ACh, DA, NE, GABA, 5-HT, Hist, Gly, Glut, Asp, NO, some hormones, ...

Autonomic Nervous System

Regulates the activities of cardiac muscle, smooth muscle, and glands which are typically involuntarily controlled.

• Preganglionic autonomic neurons originate in the CNS.

• Postganglionic neurons originate from an autonomic ganglion (a collection of neuron cell bodies located outside the CNS).

Fight-or-Flight - A mass activation of ANS by norepinephrine (NE) via postganglionic input and epinephrine (via adrenal medulla) which prepares the body for intense physical activities.

Sympathetic Division:

• Preganglionic neurons originate primarily in the thoracolumbar division (T1-L2).

• Synapse w/ postganglionic neurons in the sympathetic chain ganglia (paravertebral ganglia) or in other collateral (prevertebral) ganglia.

• Postganglionic axons are generally longer than preganglionic axons; they lead to the target organ.

• Preganglionic neurons release ACh (which binds to a cholinergic synapse); postganglionic neurons release NE (which binds to an adrenergic synapse).

Parasympathetic Division:

• Craniosacral division (cranial nerves 3, 7, 9, 10 and sacral nerves S2-S4).

• Synapse w/ postganglionic neurons in the target organs or near the target organs in the terminal ganglia

.

• Preganglionic axons are very long compared to the postganglionic neurons they innervate because the latter are confined to the target organs.

• Preganglionic neurons release ACh; postganglionic neurons release ACh.

Receptor Types:

• Adrenergic - alpha (α), beta (β); subtypes 1 and 2

• Cholinergic - muscarinic, nicotinic

Compounds have been developed that selectively bind to these receptors and either promote (an agonist) or inhibit (an antagonist) the cholinergic or adrenergic effect.

Most organs receive dual innervation by both divisions of the ANS.

The 2 divisions are usually regarded as being antagonistic.

However, the effects can be:

• Antagonistic - Effects are opposite.  Examples: Heart, pupils, ...

• Complementary - Effects are similar.  Example: Salivary gland secretion

• Cooperative (synergistic) - Effects are different, but they work together to promote one action.  Example: Male reproductive system

• Penile erection is under parasympathetic control

• Ejaculation is under sympathetic control

What about the female reproductive system?  Is it controlled in a similar way? ____________________________________________

• Some structures do not receive dual innervation and receive only sympathetic input: the adrenal medulla, arrector pili muscles in the skin, most blood vessels, and sweat glands in the skin are examples.  Regulation is achieved by variations in the firing rate of sympathetic neurons.

Medulla oblongata of the brain stem most directly controls the activity of the ANS.  However, it is also influenced by sensory input and input from the hypothalamus.