Action Potentials • Most nerves exhibit Action Potentials (APs) • Spikes of electrical activity • Almost always less than 1000 per second • Almost all neurons create APs (some retinal cells only have graded potentials)
Potential • A potential is the potential to do work. • Work requires energy. • The Second Law of Thermodynamics says that all matter spontaneously moves towards lower energy states. That is, from regions of higher potential to regions of lower potential.
Potential • There are two major types of energy: • Potential Energy which derives from the four basic forces: • Gravity • Weak force • Strong force • Electromagnetic force • Kinetic energy from moving matter • The energy that made it move can be extracted.
Potential • The two main potential energies of interest to neurologists are: • Electromagnetic potential • Opposite charges attract, like charges repel. • Concentration potential • Flow is in direction of higher concentration towards lower concentrations until equalization.
Potential • Electromotive potential • Proportional to amount of separated charges +1.5 V Test Ref (0) -1.5 V Ref (0) Test + - + -
Potential • Potential difference is the difference in the total potentials between the two measured points. • Potential is measure in volts (V) • Think of a battery, typically 1.5 or 9 V. • A 9 V battery has a higher potential than a 1.5 V battery. • Potential is additive: 3 V 0 V
Potential • Concentration gradient • Any time there is a concentration gradient, there is force trying to move ions to area of lesser concentration. Fresh water (low NaCl) Seawater (high NaCl)
Potential • If you get nothing else out of this lecture: • Opposites attract • Concentrations equalize
Cellular Potential • Because neural cell walls are porous and there are differences in ion concentrations inside and out, the inside of a neuron has a potential with respect to the extracellular fluid. • Cellular potentials are always given with respect to the extracellular space.
Cellular Potential • Potential can be calculated by the Goldman equation, which takes into account the concentrations of the ions Na+, K+ and Cl- and their membrane permeabilities.
Cellular Potential • Normal nerve potential is about –70 mV with respect to the extracellular space.~1/20 of a battery
Nerve Cell Environment A whole lots of Na+ (sodium) 0 mV A little Cl-(chlorine) Cell Lots of K+ (potassium) -70 mV Na+ K+
Nerve Cell Membrane • Populated with ion channels • 4-7 transmembrane domain proteins • Typically only pass one type of ion • Activated by ligands, voltage, or time • Types • Passive, ionic movement by gradient • Facilitated transport • Active transport, energy powered pump
Transmembrane Transport • Simple diffusion (spontaneous) • Ions follow gradients without help • Facilitated diffusion (spontaneous) • Helper proteins assist the move • Active transport (energy required) • Normally symport – 2 ions transported at once • http://pb010.anes.ucla.edu/membrane.htm
Transmembrane Transport • Simple diffusion • Ions follow gradients without help (Na+, K+)
Transmembrane Transport • Facilitated diffusion • Larger molecules follow gradients, but have to be passively assisted to pass thru membrane. Ex: glucose transporter
Transmembrane Transport • Active transport • Molecules move against a gradient, so an energy-consuming “pump” is required. • Symport – 2 ions are moved at once. (Na+-K+ pump)
Action Potential • There are many types of “holes” or channels in the neural membrane, but the most important are: • Key-activated sodium (Na+) channels • Voltage-activated sodium (Na+) channels • Voltage-activated potassium (K+) channels • Key-activated chlorine (Cl-) channels • An ATP-powered sodium-potassium pump (symport)
Action Potential • Cell at –70 mV. Normally all channels are closed. • “Something” opens keyed Na+ channels. • Na+ enters the cell, depolarizing it. • When potential reaches threshold (about -40 mV) at the axon hillock, many more voltage-controlled Na+ channels open causing a flood of Na+ depolarizing the cell to about +30 mV. • Na+ channels close and voltage-controlled K+ channels open, K+ flows out repolarizing the cell. • Na+/K+ pump restores equilibrium.
Action Potential • AP propagation • The local depolarization triggers the voltage controlled pores in the adjacent region, causing another depolarization. • The depolarization progresses along the length of the axon.
Action Potential • At the terminals, the depolarization allows Ca++ to enter the terminal and trigger fusion of neurotransmitter vesicles to the membrane. • Neurotransmitter is released via exocytosis.
Action Potential • Soluble NSF Attachment protein REceptors (SNAREs) keep vesicles in close proximity to membrane. • Ca++ causes SNAREs to complete fusion.
Action Potential • Amino acid and amine neurotransmitters are synthesized in the terminal button. • All others, including peptides and larger proteins, are manufactured in the cell body and transported to the terminal button at speeds of up to 1 meter per day. • The latter may suffer periods of insufficient neurotransmitter.
Action Potential • “All or Nothing” firing • Once threshold is reached, the nerve will always fire
Action Potential • Refractory periods • Absolute • About 1 mSec, cannot fire again. • Due to time-activated gate in Na+ channels. • Relative • About 5-10 mSec, can fire again with more stimulation. • Due to undershoot.
Action Potential • Firing rate limited to about 1000 Hz • Due to absolute refractory period • Firing rate varies with stimulation, but almost never ceases entirely • Non-quiet presynaptic neurons • Random molecular motion • Mechanical forces • Ionic leakage through nerve wall
Synapse • The space between the terminal button of a presynaptic nerve and a dendrite, dendritic spine, soma or axon of the postsynaptic cell.
Synaptic Transmission • The neurotransmitter diffuses across the synapse and binds to receptors on the postsynaptic nerve dendrites. • When enough stimulation has been received, the postsynaptic nerve fires an AP. • Presynaptic autoreceptors limit neurotransmitter release. • Excess neurotransmitter is destroyed or reuptaken into the presynaptic nerve.
Synaptic Transmission • “Something” opens receptor Na+ channels • Neurotransmitters • From presynaptic cell • Very localized action • Neuromodulators • From nearby cells • Local area, longer term action • Hormones • Transported via blood, not neurons • Systemic, long term action
Synaptic Transmission • Inhibition • Similar to how opening Na+ channels allows the nerve to depolarize towards threshold, inhibitory channels allow negative ions to enter and hyperpolarize the cell, moving potential farther away from the threshold. • Usually opens Cl- channels • GABA, Serotonin (5-HT), etc.
Synaptic Transmission • Excitory Post- Inhibitory Post-Synaptic Potential Synaptic Potential EPSP IPSP
Synaptic Transmission • Excitatory and Inhibitory Inputs • Sum spatially and temporally. • Many thousands of inputs usually necessary to reach threshold.
Action Potential • Conduction Velocity • The larger, the faster! • < 1 m/s for small, unmyelinated neurons • > 50 m/s in large myelinated neurons
Myelin • Conduction can be speeded by myelin • Segmented non-conductive sheath surrounding the neuron. • No (few) ion channels underneath the sheath. • High concentration of ion channels in the nodes between sheath segments. • AP “jumps” from one node to the next, bypassing propagation delays (known as saltatory conduction). • Can speed conduction by 100x.
Myelin • Schwann Cells in PNS • Tightly wrapped around axon. • Each segment about 1 mm, no ion channels. • Nodes of Ranvier in between.
Myelin • Oligodendrocytes in CNS • Each cell wraps several nerves. • More compact than individual Schwann cells. • Also segmented with nodes.
Postsynaptic Effects • Three main types of effects: • Direct effect on ionic channels • Second messenger systems • Direct gene activation
Postsynaptic Effects • Direct effect on ionic channels • Neurotransmitter binds to receptor channel causing a conformational change which opens the channel to allow the ion to pass. • Quickest acting and shortest acting effect. • Neurotransmitter remains in synapse and is metabolized or reuptaken.
Postsynaptic Effects • Second messenger systems • A guanine sensitive protein (G-protein) is linked to the receptor. • Neurotransmitter binds to receptor channel causing G-protein to activate a catalytic enzyme in the membrane. • The enzyme produces a “second messenger.” • The 2nd messenger can affect other receptors or can directly influence protein synthesis. • Effects are slower, but longer lasting.
Second Messengers • The most common 2nd messengers are: • Cyclic Adenosine Monophosphate (cAMP) • Inositol Triphosphate (IP3) • Diacylglyceride • 2nd Messengers: • AMPLIFICATION • PROLONGED EFFECT
Direct Gene Activation • Primarily lipid-soluable steroids • Pass through the cell and nuclear membranes. • Led to DNA by chaperonin-receptor complexes. • Receptor binds to acceptors on chromatin. • Transcription of specified protein begins. • mRNA goes to rough ER for protein synthesis.
Neurotransmitters • Trigger postsynaptic nerves • Major classes of neurotransmitters • Amino Acids • Monoamines • Acetylcholine • Soluable Gasses • Peptides • Steroids