- What is a membrane potential
- Role of synapses and neurotransmitters
- Receptors and their role
The resting membrane potential is the electrical potential of the cell at its basal state. There are two forces acting at any one time across a selectively permeable membrane, first ions moving along their concentration gradient and secondly ions moving according to their electrical gradient such as positive ions moving towards a negative charge. In the resting neuron, there is a small potassium leak. Potassium concentration within the neuron is high. The membrane is impermeable to sodium and proteins and chloride. The potassium moves out of the cell along its concentration gradient. This leads to an increasingly negative charge inside the cell which prevents further net movement. This gives us a resting potential of -60 mV. The Nernst equation is used to calculate the membrane potential. It assumes that the membrane is selectively permeable to an ion. Imagine we have 2 liquids separated by a semipermeable membrane but one side has a very high potassium concentration and the other a very low one. Both sides are electrically neutral due to the presence of other ions. When the experiment starts potassium will move down its concentration gradient. However, the high concentration side will have lost positive charge and this will try to retain potassium. Eventually, an equilibrium potential is reached. The Nernst equation defines this. All one needs is the concentration of the ions on either side of the membrane and their charge. Although changes in potassium flux are vitally important the absolute number of molecules that are involved in passing across the cell membrane is only a very tiny percentage of the total.
To cause a neuron to depolarise it needs the correct stimulation at its dendrites and the net charge on the neuronal cell membrane of perhaps tens, hundreds or even thousands of axons synapsing on dendrites will determine whether sufficient stimulus is achieved to cause an action potential to be generated. This can be by temporal excitatory summation where a series of impulses from one excitatory fibre over a period of time produce a membrane potential high enough to result in depolarisation or by spatial excitatory summation occurs when impulses in at least two excitatory fibres trigger an action potential. Note that not all stimulations are excitatory, indeed some GABA ion channels open chloride channels allowing the cell interior to become more negative and therefore hyperpolarised. Glutamate an excitatory transmitter causes depolarisation. Hyperpolarisation is either due to movement in of chloride ions or movement out of potassium ions. The extreme negative charge closes sodium channels and renders the cell refractory until the membrane potential returns to normal. With an action potential stimulates a cell sufficiently the internal voltage increases to greater than 55mV. The threshold value for depolarisation is usually about 10 mV above the resting potential. At this level there is a transient increase in Na+ permeability by voltage-gated sodium channels and this leads to Na+ movement into the cell and the inside of the cell becomes more positive which acts to cause even greater Na+ permeability with a positive feedback loop that rapidly increases the membrane potential. There follows a transient rise in potassium permeability such that it flows out of the cell making the inside more negative even more so at rest. The ions pass through voltage-gated ion channels. During an action potential, the charge inside the cell can become even more negative and this is called hyperpolarisation often due to further movement out of potassium ions which can render the cells refractory for a short period. The Nernst equation can be used to calculate resting membrane potentials. Interestingly different cells in the body have similar but not always identical resting membrane potentials e.g. neurons -70 mV, glial cells -90mV skeletal muscle cells - 80mV and smooth muscle cells -70 mV. E K = - 90 mV , E Na = + 60 mV, Resting membrane potential = - 70 mV.
Neuronal conduction is due to the passage of an action potential propagating along the axonal membrane. As one area of membrane depolarises this changes the condition for the adjacent cells and a continuous depolarisation occurs. This can be improved and speeded up dramatically by myelination which enables the depolarisation to jump from node of Ranvier to the next one. This is known as saltatory conduction. One of the earliest signs of demyelination is slowing of the transmission of axon potentials along demyelinated fibres.
Depolarisation at the axon hillock can cause an action potential to propagate as the membrane depolarises it causes the adjacent membrane to depolarise and so on until it reaches the axon terminal. This causes the activation of voltage-gated calcium channels which allows calcium to enter which causes the synaptic vesicles to fuse with the terminal membrane. Here the electrical transmission becomes chemical as neurotransmitters are released into synaptic clefts (exocytosis) and either has an effect on other neurons or muscle cells. This process of passage across the gap of 200 nm takes 0.05 ms. The gap is tiny and has been calculated as the width of a row of 200 atoms. The neurotransmitter then attaches to its post-synaptic receptor and is then released and either taken back up by the neuron or broken down.
Electrical synapses also occur within the CNS and are much narrower between adjacent cells with the distance of 2 nm involved. These are often called a nexus or a gap junction. These tend to be seen between glial cells rather than neurons. There is the passage of ions which allows depolarisation. Outside the CNS this is seen in cardiac tissue, between adjacent myocytes.
Synapses, Neurotransmitters and receptors
Most synapses between neurons are either axodendritic with the bouton applied to the dendritic spine of another neuron or axosomatic with the bouton against the cell body of another neuron. Axodendritic synapses are usually excitatory but axosomatic are usually inhibitory. The arrival of a neurotransmitter molecule at a post-synaptic receptor can have several different outcomes. It can do nothing, it can depolarise that part of the membrane of the dendrite or axon it or the effect can be hyperpolarisation. This all depends on the receptor and the neurotransmitter. There are two main classes of receptors: ionotropic which consist of a central ion channel surrounded by multiple protein subunits which deliver a very fast and specific response. The others are metabotropic receptors which involve G proteins and intracellular secondary messengers and have a more delayed response. Some neurotransmitters, for example, acetylcholine act at both types. Glutamate is the major excitatory neurotransmitter. Acts at fast ionotropic membrane receptors. It binds to NMDA receptors as well as AMPA and metabotropic glutamate receptors. GABA and glycine are the main inhibitory neurotransmitter and act at fast ionotropic GABA A membrane receptors and slow metabotropic receptors. GABA B membrane receptors are slow and metabotropic. There are many more neurotransmitters involved in brain function and any of these can be released from vesicles by a neuronal axon into the synaptic cleft to act on the post-synaptic membrane. Examples of neurotransmitters include
- Monoamines e.g. Noradrenaline, Dopamine, Serotonin, Histamine
- Acetyl choline a quaternary amine which acts at both muscarinic and nicotinic receptors
- Neuropeptides e.g. substance P
The interaction of a neurotransmitter on depolarising the area of membrane that is activated by a receptor may be an excitatory post-synaptic potential. If the neurotransmitter hyperpolarises the cell this causes an Inhibitory post-synaptic potential reducing the likelihood that the neurone with the fire of an action potential down its axon. Remember 100s or even 1000s of these may be happening at any one time. It is the summation of all these that determine neuronal response. The summation can be temporal when rapidly repeated stimuli occur during depolarisation at one terminal or spatially when stimuli are received simultaneously from adjacent terminals. In practice both are important. For interest's sake don't forget that both tetanus toxin and botulinum prevent the release of neurotransmitters. Botulinum prevents the release of Ach at the neuromuscular junction. Following binding, the neurotransmitters become free and are either degraded locally or reuptaken back into the neuron or by the glial cells where they can be reprocessed or degraded. Synapses occur at the junction between the axon and an adjacent neuronal dendritic spine or cell body. It is fascinating that the density of dendritic spines is thought to play a role in learning and memory. Sometimes the axon bouton can synapse adjacent to another axon bouton and can alter its behaviour through stimulation or what is termed pre-synaptic inhibition often mediated by GABA which opens chloride channels hyperpolarising the membrane. There may be an assumption that there is a single signal sent and then all is quiet. In practice, there is often a constant tonic level of firing and it is the change in frequency and intensity that changes. The frequencies can be from up to 100 Hz at some junctions. The firing pattern can itself carry information.
There is evidence that synapses can change 'Plasticity' depending on the degree and frequency of stimulation. This can be seen by changes in the post-synaptic thresholds. May play a role in memory. To make changes the stimulus must be strong such as due to multiple simultaneous inputs. There should be the resultant firing of the post-synaptic action potential. Calcium flux appears to be important. Plasticity can be short and long-term.