Signal Transduction Mechanisms: Electrical Signals in Nerve Cells Most animals have nervous system that : 1) collects information, 2) processes information and 3) elicits responses to the information. Neurons are specially adapted for the transmission of electrical signals. o The cell body bears the nucleus and organelles. o The dendrites receive (and combine) signals. o The axons conduct signals. o The myelin sheath surrounds the axon in a discontinuous manner (form the nodes of Ranvier). Nerve cells can be long (e.g., a motor neurons 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 Every cell in the body is electrically active: to a greater or lesser degree, they all pump ions across the cell membranes to maintain an electrical potential difference across the membrane. This difference in electrical charge between the inside and outside of the membrane is the basis for many types of physiological processes, including transport of particles across the membrane and signalling among cells. In some cells up to 40% of energy is used to power active transport, a process that maintains or restores membrane potentials.
Membrane potential is a property of all cells andreflects a difference in charge on either side of the cell membrane. Normally, cells are net negative inside thecell which results in the resting membrane potential or Vm (a negative resting membrane potential).
The resting membrane potential depends on differing concentrations of ions inside (cytoplasm) and outside the membrane (extracellular fluid). Large negatively charged molecules (proteins, RNA) do not pass through the membrane to set up the negative resting membrane potential.
If the cell membranes were simply permeable to these ions, they would approach an equilibrium with equal concentrations on each side of the membrane, and no voltage difference. But there is a voltage difference, so the processes which produce the membrane potential are not simply diffusion and osmosis. Electrical excitability depends upon “ion channels” acting like gates for the movement of ions through the membrane to produce an action potential. In passive channels, ions may freely move diffusively through the channel. Leakage channels are the simplest type, since their permeability is more or less constant. Chemically gated channels pump Na+ (and some Ca+2) out of the cell, while pumping in K+ in the ratio of 2 K+ for every 3 Na+ pumped out. 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.
Nerve, muscles and some glands share electrical excitability which, in response to stimuli, causes rapid changes in membrane potential (action potential) to occur. Within a millisecond, the membrane potential changes from negative to positive and back. In neurons, the action potential moves down the axon as a nerve impulse.
Steady-state movement of ions define the membrane potential and is maintained by the Na+- K+ pump. In the resting state of a neuron, the inside of the nerve cell membrane is negative with respect to the outside. The voltage arises from differences in concentration of the K+ and Na+ ions. Depolarization (or a lowering of the membrane potential) results from flow of positive sodium ions into the cell.
In nerve cells, a neurotransmitter can affect the activity of a postsynaptic cell via 2 different types of receptor proteins: ionitropic or ligand-gated ion channels, and metabotropic receptors. 1. Ligand-gated ion channels combine receptor and channel functions in a single protein complex. 2. Metabotropic receptors usually activate G-proteins, which modulate ion channels directly or indirectly through intracellular effector enzymes and 2nd messengers.
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. Recovery from an action potential is partly dependent on a type of voltage-gated K+ channel which is closed at the resting voltage level but opens as a consequence of the large voltage change produced during the action potential.
Voltage-gated Ion Channels
The resting potential of a neuron is -70 to -80 mV. Action potentials propagate electrical signals along an axon. Initially, a resting neuron is made ready for electrical activity through the balance of ion gradients and membrane permeabilities. More depolarization causes the membrane to A small amount of reach the threshold potential at which the nerve depolarization cell membrane rapidly changes electrical (<+20mV) will properties and ion permeability to initiate an normally result in action potential. recovery without The action potential is a brief depolarization/ effect. repolarization that propagates from the site of origin.
Graded potentials are short lived Graded Potentials depolarizations or hyperpolarizations of an area of membrane. These changes cause local flows of current that decrease with distance. The more intense the stimulus, the more ion channels that are opened, and the greater the voltage change.
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. Sub-threshold depolarization results in no action potential generated, which is at least partially due to the outward movement of K+ ions. If the K+ ion exit cannot compensate for the influx of Na+ ions, the membrane reaches the threshold of depolarization. When the voltage-dependent Na+ channels open, Na+ flows in during the depolarizing phase. Once the membrane potential peaks, the repolarizing phase begins with the inactivation of the Na+ channels (blocking the Hodgkin cycle) and the opening of the voltage-gated K+ channels.
The recovery is due to the passive movement of ions- not the action of the Na+/K+ pumps. During the absolute refractory period (~few milliseconds), Na+ channels cannot be opened by depolarization and no action potential can be generated. During the hyperpolarizing phase, the Na+channels are reactivated but Na+ flow is opposed by K+ currents which produces a relative refractory period.
1.The passive spread ofAction potentials are propagated depolarization causes along the axon without losing cations (mostly K+) to strength by active propagation: spread to adjacent regions of the axons cytoplasm. 2.As the depolarization spreads, it loses its magnitude and MUST be actively propagated to move far. 3.Propagation depends upon the passive spread of depolariza- tion to induce the membrane potential in adjacent parts of the axon to reach the threshold potential which then triggers the intake of Na+ ions and continuation of the cycle.
For example, signals move from the dendrites 4.At the axon hillock, athrough the cell body to the base of the axon great influx of Na+ (the axon hillock) where Na+ channels are ions can occur which concentrated. specify that action potentials initiated here are propagated down the axon. The propagated action potential is the nerve impulse. 5.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 hyperpolarizing phase results from the increased permeability of K+ due to the open voltage-gated K+ channels. The membrane potential returns to resting state with the closing of the voltage-gated K+ channels. Hyperpolarization prevents the neuron from receiving another stimulus during this time, or at least raises the threshold for any new stimulus. Hyperpolarization also prevents any stimulus already sent up an axon from triggering another action potential in the opposite direction. It assures that the signal is proceeding in one direction. After hyperpolarization, the Na+/K+ pump eventually brings the membrane back to its resting state of -70 mV .
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.
SYNAPSE Synapses are specialized junctions through which NS cells signal to one another and to effectors(muscles or glands). They provide the means through which the NS connects to and controls the other systems of the body.
Nerve cells communicate with muscles, glands and other nerve cells via synaptictransmission. In an electrical synapse, the axon of the presynaptic neuron connects to the dendrite of postsynaptic neuron by gap junctions.
In a chemical synapse, the presynaptic and postsynaptic neurons areseparated by a gap, the synaptic cleft.
A NEUROTRANSMITTER is a small molecule that, through the interaction with a specific receptor, relays a signal across nerve synapses. Neurotransmitter molecules that are kept in the terminal bulbs or synaptic knobs aresecreted into the synaptic cleft and then bind to receptors in the postsynaptic neuron. This generates an electrical signal to stimulate or inhibit a new action potential.
A neurotransmitter must: 1) cause a response when injected into the synaptic cleft, 2) occur naturally in the presynaptic neurons and 3) be released when the presynaptic neurons are stimulated. An An inhibitory excitatory neuro- neuro- transmittertransmitter causes causes hyperpola- depolari- rization in zation the post- synaptic neuron.
Neurons can integrate both excitatory and inhibitory signals from other neurons. The summation of synaptic inputs leads to whether or not an action potential is formed in the postsynaptic neuron.
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 K+ 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 neurons 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 by specific receptors on postsynatic neurons such as ligand-gated channels.The acetylcholine receptor is a ligand-gated sodium channel that binds two molecules of acetylcholineto open. This receptor is specifically bound by snake venom components (alpha-bungarotoxin and cobratoxin).
The GABA (gamma-aminobutyric acid) receptor is a ligand-gated Cl- channel which produces an influx of Cl- ions in the postsynaptic neuron. The entry of Cl- ions neutralize the effect of Na+ 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).
Brain images showing decreased dopamine (D2) receptors in the brain of a person addicted to cocaine versus a nondrug user. The dopaminesystem is important for conditioning and motivation, and alterations such as this are likely responsible, in part, for the diminished sensitivity to natural rewards that develops with addiction.