MEMBRANE POTENTIALS
Ions are charged atoms or molecules.
Cations carry one or more positive charges
Anions carry one or more negative charges.
Like charges repel and unlike charges attract. An ion can thus
exert a force on another ion.
Work = a force x a distance
If ions are separated (i.e. they are some distance apart), they have the POTENTIAL for doing work.
VOLTAGE is a measure of the potential of separated charges for doing work.
[see Figure]
Every living cell has a membrane (resting) potential. These result from the diffusion of ions across the membrane and they are negative by convention (the inside is negative relative to the outside).
Resting potentials typically range from -10 to -100 mV (millivolts).
The membrane potential ultimately depends on the distribution of ions between the ICF and the ECF. These distributions, in turn, depend on the differential permeability of the membrane to different ions, on the presence of nondiffusible ions, on the action of the Na/K ATPase pump, and on the electrochemical properties of the membrane itself.
[see Animation]
[Fig. 6-10] An equilibrium potential will be established if we have a membrane which is permeable to potassium but not to sodium.
(keep in mind that potassium is high inside a living cell and sodium is high outside)
[see Figure] Note that for a typical resting potential of -70 mV (A in the above figures), the electrical and chemical forces acting on potassium are in opposite directions, whereas those for sodium are in the same direction.
[Fig. 6-12]
The resting potential is influenced by the presence of nondiffusible ions (i.e. by proteins, which tend to have a net negative charge, and which, because of their large size, are not able to diffuse outwards).
This contributes to the inside negativity of the membrane. The magnitude of this effect can be predicted from the Donnan (or Gibbs - Donnan) Equilibrium.
The sodium/potassium pump acts to maintain the resting potential by continuously pumping out sodium that enters the cell and replacing potassium that leaks out.
However, the pump also directly contributes to the charge separation because it transports the two ions unequally (i.e. it pumps three sodium ions out for every two potassium ions that it brings in). It thus has a direct ELECTROGENIC effect.
[see Figure]
The plasma membrane, by virtue of its chemical composition and structure, helps to maintain an electrical potential.
The membrane has a high electrical resistance and also a large capacitance (i.e. ability to hold a potential). This latter property is related to the thinness of the membrane (capacitance increases as membrane thickness decreases).
The NERNST EQUATION allows us to predict the magnitude of an equilibrium diffusion potential from a particular distribution of ions.
The transmembrane potential (E) = (2.3 RT/zF) log ([C1]/[C2])
Where R = the gas constant, T = absolute temperature, z = valence, F = Faraday's number, and [C] = ionic concentration.
Fortunately, we can simplify this by considering only univalent ions, by holding temperature constant (e.g. at 25 C), and by combining the gas constant and Faraday's number.
(for a cation): E = -59 log ([Ci]/[Co])
(for an anion): E = +59 log ([Ci]/[Co])
Now, recall the typical concentrations for the three major ions:
Sodium (ECF = 150, ICF = 15)
Potassium (ECF = 5, ICF = 150)
Chloride (ECF = 110, ICF = 4)
For sodium:
E = -59 log (15/150) = -59 log (0.1) = +59 mV
For potassium:
E = -59 log (150/5) = -59 log (30) = -87 mV
For chloride
E = +59 log (4/110) = +59 log (0.036) = -85 mV
(NOTE: log 0.1 = -1.0, log 30 = +1.48, log 0.036 = -1.44
The measured potential for a living cell (-70 mV) is very different from the predicted equilibrium potential for sodium. We can thus conclude that the diffusion of sodium contributes little to the resting potential. In contrast, the predicted potentials for both potassium and chloride are reasonably close to -70 mV.
Are either (or both) of these important?
To find out, we can experimentally manipulate the [ECF]. Changing [chloride] has little effect on the measured membrane potential (thus suggesting that chloride does not play a major role).
However, we find that the measured and predicted potentials for potassium agree quite well. The resting potential of a cell is thus PRIMARILY a potassium diffusion potential.
[see Figure]
The undisturbed cell is much more permeable to potassium than to sodium. The ratio is on the order of 30 : 1.
Cells contain both gated and non-gated (aka open or "leak") channels for both ions, but far more non-gated channels for potassium than for sodium.
[see Figure]
[Fig. 6-13]
(a) The Na+/K+ ATPase pump establishes an unequal distribution of ions and the basis for a resting potential.
(b) The electrogenic effect of the pump contributes to the potential.
(c) At a steady state, there is a balance between ion pumping and ion fluxes through membrane channels.
ACTION POTENTIALS
Excitable cells (i.e. nerve and muscle cells) can rapidly alter their membrane potential and then quickly restore it to the resting level.
The stimulation of such a cell results in a sudden dramatic (but short-lived) increase in sodium permeability followed by an increase in potassium permeability. These changes result from the opening and closing of gated ion channels.
[Fig. 6-19] The abrupt rise and fall of the membrane potential is sometimes referred to as a "spike". The rise represents a depolarization and the fall a repolarization.
Note the abrupt, but short-lived, increase in sodium permeability and the somewhat delayed (and lesser) increase in potassium permeability.
[Fig. 6-21] An action potential will not occur unless the depolarization reaches THRESHOLD. However, once threshold is reached, a POSITIVE FEEDBACK situation is established.
Subthreshold responses are GRADED and localized. Action potentials, in contrast, are propagated ALL OR NONE responses.
PROPERTIES OF STIMULI
[see Figure] The RHEOBASE is the minimum voltage needed to get a response. The
CHRONAXIE is the stimulus duration needed to get a response when the stimulus strength is equal to twice the rheobase.
REFRACTORY PERIOD
There is a period of time, following the application of a stimulus, during which a second stimulus (of the same magnitude) will fail to evoke a response.
The initial period is the ABSOLUTE REFRACTORY PERIOD, during which NO stimulus will produce a response. This is followed by the RELATIVE REFRACTORY PERIOD, during which a response is possible, but only with a stronger than original stimulus.
Action potentials would be of relatively little interest if they were merely isolated local events. Fortunately (for life as we know it) the depolarization can be propagated along the membrane of the excitable cell.
Membrane depolarization at one region produces a local current (ion) flow, which depolarizes adjacent regions of the membrane. The action potential is thus propagated, in either direction, away from the original point of stimulus. The action potential cannot reverse direction because of its refractory period.
[see Fig. 6-22]
[see Animation]
The propagation of a nerve impulse involves only a very small fraction of the total available ions. Recovery is very rapid, and, under usual physiological conditions, a nerve fiber (i.e. neuron) can not be fatigued.
A nerve impulse is propagated WITHOUT DECREMENT (i.e. it does not get smaller as it moves further away from the point of origin). This does not violate the Second Law of Thermodynamics, because the energy for the conduction comes from within (not from the stimulus). At every point, the action potential is ALL OR NONE.
An instrument such as a cathode ray oscilloscope can be used to record action potentials. This device monitors the electrical potential (between two recording electrodes).
The action potential we examined earlier was recorded INTRACELLULARLY (i.e. one electrode inside the cell and the other on (or near) the outer membrane surface. Alternatively, we can measure action potentials EXTRACELLULARLY (i.e. both electrodes on the surface).
The resting potential will be about -70 mV if recorded intracellularly, but will be zero if recorded extracellularly.
[see Figure] NOTE: In the laboratory, we will be recording COMPOUND action potentials, and we will switch recording electrodes so that the first peak is up and the second down.
If we crush the nerve (neuron), or otherwise prevent the action potential from reaching the second recording electrode, we will see a MONOPHASIC rather than a DIPHASIC recording.
CONDUCTION VELOCITY
The conduction velocity of a nerve impulse can vary from as little as 0.1 m/g (e.g. in a sea anemone) to as much as 120 m/s in a human (or other mammal). There is great variation even within a species (i.e. from 0.5 to 120 m/s in humans).
In general, the greater the diameter of a neuron, the faster its conduction velocity.
Certain neurons of vertebrates can achieve very high conduction velocities because they are MYELINATED (i.e. surrounded by a layer of fatty material known as myelin). This effectively insulates (electrically) the surface of the neuron. However, the myelin sheath is interrupted periodically by non-insulated NODES OF RANVIER.
Conduction in myelinated fibers is SALTATORY (i.e. it "jumps" from node to node), and the velocity may be up to 50x as fast as those of nonmyelinated fibers.
[see Figure]
[see Figure]
[Figs. 6-2a; 6-2c]
[see Animation]
For myelinated fibers, conduction velocity (v) is approximately proportional to the diameter of the fiber. In contrast, the conduction velocity for a nonmyelinated fiber is approximately proportional to the square root of its diameter.
Myelinated: v is proportional to d (where d = diameter)
Nonmyelinated: v is proportional to the square root of d
[see Figure] Below a certain size, it is actually advantageous for a neuron to be nonmyelinated. Nevertheless, myelin allows small neurons to conduct action potentials very rapidly.
Some animals (such as the squid and the earthworm), which lack myelin, have achieved rapid conduction velocities (i.e. 30 to 35 m/s) by developing giant nerve fibers.
Myelin, however, is a great "invention". It allows relatively small neurons to conduct up to 120 m/s.
The human optic nerve has a diameter of about 3 mm. It contains a large number of myelinated neurons and carrier a great deal of "information" to the visual cortex of the brain.
It has been calculated that in order to carry the same amount of information at the same velocity without myelination, we would require an optic nerve 300 mm in diameter.
NEURON (NERVE CELL)
[Fig. 6-1] The neuron is the fundamental unit of the nervous system.
What we see anatomically as a "NERVE" is actually a cable-like arrangement of thousands of individual neurons (plus associated connective tissue).
A nerve is typically a mixture of a variety of neurons of different types (some myelinated and some non-myelinated).
The conduction velocities of the individual neurons within a single nerve may vary greatly (depending on fiber diameter and the presence or absence of myelination).
The action potential recorded from a nerve (as opposed to a single neuron) is called a COMPOUND ACTION POTENTIAL.
[see Figure]
There are three functional categories of neurons:
Afferent (sensory) neurons carry information TOWARDS the CNS
Interneurons carry information WITHIN the CNS
Efferent (motor) neurons carry information AWAY FROM the CNS
NOTE: Some authorities consider all efferent neurons to be motor neurons. However, others consider only somatic motor efferents (i.e. efferents that control skeletal muscle) to be motor neurons.
[see Figure] The distinction between axons and dendrites is clear for a motor neuron, but not so obvious for sensory and interneurons. It is helpful to remember, however, that the normal direction of impulse transmission is always from dendrite to axon.
SYNAPSE
A synapse is a functional connection between two excitable cells accomplished through contact (or near contact) of their membranes.
Though some would restrict this term to neuron-neuron connections, it seems more reasonable to include all connections between excitable cells (i.e. both nerve cells and muscle cells).
With this more inclusive definition, we find three categories (and five types) of synapses:
e.g. a neuromuscular junction
e.g. junctions beween adjacent cardiac or smooth muscle cells
These morphological types of synapses can alternatively be categorized into two functional (physiological) types:
ELECTRICAL SYNAPSES:
These pass an electric signal directly (via gap junctions) from the cytoplasm of one cell to that of an adjacent cell. These are relatively uncommon and occur mainly between giant axons and large motor axons in some invertebrates and, in vertebrates, between some cells within the CNS and retina plus in cardiac and smooth muscle.
CHEMICAL SYNAPSES
The vast majority of synapses are of the chemical type. These synapses use specific chemicals called NEUROTRANSMITTERS to carry information from one excitable cell to another.
With respect to a particular synapse:
The neuron releasing the neurotransmitter is called the PRESYNAPTIC NEURON and that receiving the neurotransmitter is called the POSTSYNAPTIC NEURON.
[Fig. 6-25] Neurotransmitter is released (via exocytosis) from the synaptic vesicles of the presynaptic cell. The chemical diffuses across the synaptic cleft and attaches to receptors on the postsynaptic membrane, where it may induce excitatory or inhibitory changes in the polarity of the postsynaptic membrane.
[Fig. 6-24] The multibranched terminals of a single presynaptic neuron can synapse with dozens of different postsynaptic neurons (DIVERGENCE). Each postsynaptic neuron, in turn, receives synaptic input from dozens of different presynaptic neurons (CONVERGENCE).
Given the fact that we have several billion neurons, and that each may receive input from 100 or more neurons and send output to 100 or more other neurons, the total number of synapses is astronomical.
A recent estimate suggests that there might be as many as 100 trillion synapses in a human CNS!
[see Figure]
POSTSYNAPTIC POTENTIALS
An EXCITATORY POSTSYNAPTIC POTENTIAL (EPSP) results in a slight depolarization of the postsynaptic membrane. The activation of the receptor by the neurotransmitter typically results in an increased permeability to sodium and other small cations. This results in a net movement of positive ions into the cell and brings it closer to threshold.
An INHIBITORY POSTSYNAPTIC POTENTIAL (IPSP) is a hyperpolarization of the postsynaptic membrane resulting from a neurotransmitter induced increase in chloride (or potassium) permeability. This moves the potential further away from threshold.
[see Animation]
NEUROTRANSMITTER RELEASE
Neurotransmitter release is ultimately triggered by an action potential moving down the presynaptic cell to the axon terminal. The resulting depolarization of the axon terminal opens voltage-gated calcium channels in the presynaptic membrane. The calcium ions diffuse to the vicinity of the synaptic vesicles docked at the membrane adjacent to the synaptic cleft. This triggers exocytosis of the vesicle contents.
COTRANSMITTERS AND NEUROMODULATORS
The postsynaptic responses can be rather diverse. Sometimes more than one neurotransmitter is released at a single synapse. The separate chemicals are then called COTRANSMITTERS.
Some chemical messengers are best described as NEUROMODULATORS. These do not produce the typical EPSPs or IPSPs. Rather, they modify the responsiveness of the postsynaptic cell or alter the activity of the presynaptic cell. Unlike neurotransmitter action, the changes may be slow and long-lasting.
[Table 6-6 (modified)]
NEUROTRANSMITTERS
Classes of Neurotransmitters (or Neuromodulators)
1. Nitric Oxide
SPECIAL CHARACTERISTICS OF A CHEMICAL SYNAPSE
This allows for the possibility of repetitive discharge.
An action potential can travel either way along an axon from the point of stimulus, but only in one direction across a chemical synapse.
The output may be quite different from the input due to factors such as SUMMATION and INHIBITION.
A single EPSP will NOT produce an action potential in the
postsynaptic neuron. Each EPSP (or IPSP) is a LOCAL and GRADED response. The change in the postsynaptic cell will get smaller as the distance from the synapse increases (electrotonic transmission). This is quite different from the ALL OR NONE response of an action potential.
The AXON HILLOCK (and adjacent INITIAL SEGMENT) of the axon has the lowest threshold (i.e. is the easiest region to bring to threshold). It is the integrated input to this region (i.e. the sum of all EPSPs and IPSPs) that determined whether or not an action potential will result.
[see Figure]
[Fig. 6-32] A single EPSP (A) will result in a small depolarization of the initial segment. A single IPSP (B) will result in a small hyperpolarization of the initial segment.
[Fig. 6-31] The inputs reaching the initial segment can summate (i.e. add together) over time (with repetitive stimulation of a single synapse) or over space (with simultaneous input from multiple synapses). The former is called TEMPORAL SUMMATION and the latter is called SPATIAL SUMMATION.
[see Figure] IPSPs can prevent triggering of the initial segment, but can be overcome if there are enough EPSPs.
REFLEX
A reflex is a basic unit of integrated neural activity. The simplest neural reflexes are MONOSYNAPTIC. These consist of a sensory receptor, an associated afferent neuron, synaptic connections with an efferent neuron, the efferent neuron, and an effector (e.g. skeletal muscle). Stretch reflexes (such as the clinical "knee jerk reflex") are the only examples of monosynaptic reflexes in the human body.
Most reflexes are POLYSYNAPTIC (i.e. they have one or more interneurons between the afferent and the efferent.
[see Figure] This represents a monosynaptic reflex. Note that, even with this simple reflex, there are multiple alternations between local graded potentials and action potentials.
Most of the reflexes to voluntary (skeletal) muscle are either NOCICEPTIVE (i.e. responses to harmful, or potentially harmful, stimuli) or PROPRIOCEPTIVE (i.e. reflexes involved in balance, coordination, posture, locomotion, etc.). These latter reflexes can be "learned" (e.g. as when we learn to ride a bicycle or to ice skate or whatever).
The neural reflexes of vertebrates involve the central nervous system (i.e. the brain and spinal cord).
The afferent fibers of spinal reflexes always enter the DORSAL ROOT of the spinal cord. The interneurons are within the spinal cord. There are typically ascending and descending fiber tracts (carrying information to the brain and to more posterior regions of the spinal cord). Efferent fibers exit the spinal cord at the VENTRAL ROOT.
[see Figure]
RECIPROCAL INNERVATION
Actual reflex responses are often rather complex. Skeletal muscles exist in ANTAGONISTIC PAIRS (i.e. they "work against" one another). For maximum effectiveness, we should inhibit one member of the pair as we excite the other (in order to keep them from working against one another).
INHIBITION OF SKELETAL MUSCLE
Many invertebrates (e.g. crustaceans, etc.) have inhibitory neurons that DIRECTLY inhibit skeletal muscles.
In vertebrates, however, inhibition of skeletal muscle is CENTRAL (and thus indirect). We do NOT inhibit skeletal muscle directly. Rather, we inhibit the efferent neuron controlling that muscle.
[see Figure]
RECEPTORS AND GENERATOR POTENTIALS
A STIMULUS represents a change in the environment. Neurons conduct action potentials. They do NOT conduct stimuli per se. Receptors are nerve endings or specialized cells or organs which TRANSDUCE an environmental energy change to a membrane potential change and hence to a coded pattern of action potentials. The potential associated with stimulation of a receptor is known as a GENERATOR (or RECEPTOR) POTENTIAL.
Unlike action potentials, generator potentials are graded and localized responses. The magnitude of the generator potential reflects the intenstiy of the stimulus. Generator potentials are variable in duration and have no refractory period.
If of sufficient magnitude, a generator potential will elicit a burst of action potentials in the associated axon. The pattern and frequency of these action potentials will reflect the amplitude and duration of the generator potential.
Thus: A weak stimulus will evoke a low amplitude generator potential, which will produce a low frequency pattern of action potentials. In contrast, a strong stimulus will evoke a stronger generator potential and hence a higher frequency burst of action potentials.
Information about the stimulus is thus CODED as a pattern of action potentials. This is FREQUENCY (i.e. "FM") CODING. When this information reaches the CNS (e.g. the brain), it can be DECODED.
Stimuli often affect several receptors in a particular receptive field. These receptors may have different sensitivities, so, as the stimulus gets stronger, it may activate (i.e. RECRUIT) additional receptors. Also, those receptors closest to the point of stimulus will tend to respond most strongly.
By processing signals coming from many adjacent receptors, the CNS can obtain fairly detailed information about the nature and location of the stimulus.