Human Physiology Study Guide Synapse Neurotransmitters Toxins

Where is an action potential initiated in a neuron or sensory receptor?

a.     Spike initiation zone is sensory nerve endings and axon hillock

b.     An action potential is generated usually at the axon hillock, where the axon originates from the soma

c.     Typical neuron (pyramidal cells): dendrite tree and one axon

                                               i.     Action potential initiated at beginning of neuron at axon hillock

d.     Sensory neuron: cell body in middle of axon

                                               i.     Action potential initiated from nerve ending

e.     Due to different shapes of the neurons, action potentials initiated at different locations

What is the morphological difference between a somatic sensory neuron and other neurons?

a.     Axon originates from the soma at the axon hillock

                                               i.     Pyramidal cells

b.    Typical neuron (pyramidal cells): dendrite tree and one axon

                                               i.     Action potential initiated at beginning of neuron at axon hillock

c.     Sensory neuron: cell body in middle of axon

                                               i.     Action potential initiated from nerve ending

d.   Due to different shapes of the neurons, action potentials initiated at different locations

How does a neuron maintain direction, speed, and fidelity of action potentials?

a.     Direction is determined by inactivation property of sodium gated channels: can only go one way/cannot backfire

b.     The refractory period prevents backward conduction

c.     Speed and fidelity:

                                     i.     Invertebrates: increased axon diameter, high abundance of ion channels

                                    ii.     Vertebrates: myelin

1.     Myelin decreases capacitance and increases electrical resistance across cell membrane

d.     Direction (one-way, no backfire), speed (fast), fidelity (no loss of signal)

What are the two types of refractory periods, and what molecular events determine the refractory periods?

a.     Absolute refractory period: Na+ channels are inactivated, no action potential can be induced

b.     Relative refractory period: Na+ channels are out of inactivated state, but K+ channels remain open, the membrane will require a greater stimulus to cause an action potential

What are the different strategies/adaptations in invertebrates and vertebrates to increase action potential speed along axons?

a.     Invertebrates: increased axon diameter, high abundance of ion channels

b.     Vertebrates: myelin sheath (speed increases with axon diameter)

                                               i.     Made by glia (oligodendrocytes in CNS, Schwann cells in PNS)

What is the saltatory conduction of action potential along the axon? Structural basis?

a.     Conduction proceeding by leaps rather than gradual transitions

b.     Action potentials are formed at and jump from one node of Ranvier to the next; only the nodes have voltage gated Na+ channels

                                       i.     Node of Ranvier is gap in myelin sheath

What is multiple sclerosis?

a.     Myelin-forming oligodendrocytes are the targets of inflammatory and immune attacks; when this myelin is damaged, nerve impulses are slowed down or stopped

b.     Caused by damage to the myelin sheath by the immune system

What is a synapse? What distinguishes electrical from chemical synapses?

a.     Information transfer at a synapse

b.     Plays role in all the operations of the nervous system

c.     Sending cell: Presynaptic neuron, receiving cell: postsynaptic neuron, connection between cells: synapse

d.     Chemical and electrical synapses

                                               i.     Electrical synapses: electrical current flows from one neuron to another via gap junctions, allow very fast transmission

                                             ii.     Chemical synapses: chemical neurotransmitter carries information across the synaptic cleft, Slower but have flexibility (plasticity)

                                           iii.     Most synapses are chemical synapses, however, electrical synapses are found in all nervous systems, including the human brain

What are the cellular events from action potential to neurotransmitter release (in particular, functions of SNARE proteins and synaptotagmin)?

a.     Action potential depolarizes the axon terminal  The depolarization opens voltage gated Ca2+ channels, and Ca2+ enters the cell  Calcium entry triggers exocytosis of synaptic vesicle contents  Neurotransmitter diffuses across the synaptic cleft and binds with receptors on the postsynaptic cell  Neurotransmitter binding initiates a response in the postsynaptic cell

b.     The vesicle moves to the active sone and attaches reversibly  the interaction of v-SNARE and t-SNARE proteins dock the vesicle reversibly  Ca2+ enters with depolarization and binds to synaptotagmin  Ca2+ bound synaptotagmin triggers membrane fusion and exocytosis

c.     Pre-synaptic neurons release neurotransmitter from their axon terminals >

d.     The action potential induces Ca²⁺ influx through opening voltage-gated Ca²⁺ channels > Ca²⁺ binds to synaptotagmins on synaptic vesicles, which causes SNARE proteins to change conformation and induces membrane fusion > Reversible vesicle docking involves the interaction between vesicular v-SNARE and terminal-membrane t-SNARE > Complete fusion or “kiss-and-run” > Neurotransmitter diffuses across the synaptic cleft and binds to receptors on post-synaptic neurons

e.     Synaptotagmin is Ca2+ sensitive protein

                     i.     After binding, indices v-SNARE and t-SNARE binding to each other for exocytosis

What are the three mechanisms to remove neurotransmitters from the synaptic cleft?

a.     Diffusion of the transmitter from the cleft (taken away by astrocytes)

b.     Degradation of the transmitter by enzymes

c.     Reuptake into the pre-synaptic cells for reuse (can be part of like ACh or whole like serotonin?)

Know the locations and functions of common neurotransmitters (ACh, glutamate, GABA, dopamine, serotonin, substance P).

a.     ACh: neurotransmitter in spinal cord neurons to control muscles and many brain neurons to regulate memory; mostly excitatory

b.     Glutamate: most common excitatory neurotransmitter in the brain

c.     GABA: major inhibitory neurotransmitter in the brain

d.     Dopamine: pleasure neurotransmitter released by brain reward system, usually inhibitory

e.     Serotonin: neurotransmitter involved in mood, appetite, sensory perception, in spinal cord, inhibitory in pain pathways

f.      Substance P: neuropeptide involved in pain sensation

g.     ! Depolarization = excitatory (increases chance of action potential), Hyperpolarization = inhibitory (decreases chance of action potential)

h.     Glycine and norepinephrine?

What are the two major types of neurotransmitter receptors? (categorize the receptors learned in our class, nAChR, mAChR, NMDA and AMPA receptors of glutamate)

a.     Ionotropic receptor: ligand gated ion channels with the neurotransmitter as the ligand

                                               i.      nAChR, NDMA, AMPA

1.     AMPA receptor: Opened by glu, Allows Na+ influx

2.     NMDA receptor: Opened by 1) glu 2) depolarization, Allows Na+ and Ca2+ influx

b.     Metabotropic receptor: binding of a neurotransmitter to this receptor activates a signal transduction pathway in the postsynaptic cell involving a second messenger

                                               i.     mAChR

Using acetylcholine as an example, describe the synthesis, release, degradation, and different types of neurotransmitter receptors

a.     nAChR: ligand-gated ion channel in skeletal muscle

b.     Na+ and K+ flow when activated, Vm is depolarized, increased excitability

c.     mAChR: GCPR in the heart (pacemaker)

d.     K+ flow when activated, Vm is hyperpolarized, decreased excitability

e.     NMJ is the synaptic contact between axon terminal of motor neuron and the muscle fiber it controls, active zone is pre-synaptic site of neurotransmitter release, end plate is post-synaptic folds at muscle membrane

f.      Action potentials in the motor neuron cause ACh release into NMJ, muscle contraction follows release of ACh into muscle fiber

g.     ACh vesicles merge into terminal membrane, ACh exocytosis occurs, ACh receptors (nAChR & mAChR), then cause Na+ influx, which if large enough, triggers action potential on muscle fiber

h.     Reuptaken as acetate + choline

i.      Acetylcholine (ACh) is made from choline and acetyl CoA > in the synaptic cleft, ACh is rapidly broken down by the enzyme acetylcholinesterase (AChE), Acetylcholine is broken down to choline and acetate by AChE > choline is transported back into the axon terminal by cotransport with Na+ > recycled choline is used to make more ACh

What are EPSP and IPSP? How do they differ from an action potential?

a.     Excitatory postsynaptic potential (EPSP): graded depolarization that moves the membrane potential closer to threshold for firing action potential (excitement), Na+ or Ca2+ channels involved

b.     Inhibitory postsynaptic potential (IPSP): graded hyperpolarization that moves membrane potential further from threshold for action potential firing (inhibition), K+ or Cl- channels involved

c.     EPSP/IPSP is a change in the distance to the threshold of an action potential firing, not the action potential itself

                                               i.     Either create or diminish the environmental requirements for an action potential to fire

  What are spatial and temporal summations of postsynaptic potentials?

a.     If location same, summation is by time [temporal summation]

                                               i.     If two subthreshold potentials arrive at the trigger zone within a short period of time, they may sum and initiate an action potential

                                             ii.     When two post-synaptic potentials are produced in rapid succession

b.     If time same, summation is by location [spatial summation]

                                               i.     Occurs when the currents from nearly simultaneous graded potentials combine

                                             ii.     Post-synaptic potentials produced nearly simultaneously by different synapses on the same postsynaptic neuron add together

c.     The combination of post-synaptic potentials through spatial and temporal summation may trigger an action potential (when passing the threshold)

Describe the molecules involved and the cellular events of LTP (and LTD).

a.     Glutamate binds to AMPA and NDMA channels > net Na+ entry through AMPA channels depolarizes the postsynaptic cell > depolarization ejects Mg2+ from NDMA receptor-channel and opens channel > Ca2+ enters cytoplasm through NDMA channel > Ca2+ activates second messenger pathways > paracrine from postsynaptic cell enhances glutamate release

                                               i.     Once calcium enters the cell, increase presence of AMPA

1.     More AMPA receptor, increase in glutamate release, new dendritic spines

a.     Next action potential, more glutamate released, more membrane receptors

a.     Glutamate, the principal excitatory neurotransmitter in brain, is the neurotransmitter involved in LTP.

b.     Glutamate binds to and opens both NMDA- and AMPA-type receptors.

c.     Summation of excitatory postsynaptic potential causes the influx of Ca2+, which recruit more AMPA receptors at the postsynaptic membrane.

d.     Next time if this synapse is activated, more AMPA receptors at the postsynaptic membrane will lead to bigger response – memory is formed.

e.     Paracrine from postsynaptic cell enhances glutamate release from the presynaptic axon.

f.      LTP also promotes the formation of new synapses.

g.     Overall, LTP leads to more and strengthened synapses.

h.     LTD is the reverse process of LTP – loss of AMPA receptor due to the lack of stimulation.

What are the symptoms in neurons and muscles of hyperexcitability or hypoexcitability?

a.     Hypoexcitability: lack of action potentials, muscle paralysis/loss of muscle function

b.     Hyperexcitability: spontaneous action potentials, muscle cramp/spasm/sudden and involuntary contraction

Why is lidocaine used as a dental or local anesthetic?

a.     Blocks voltage gated sodium channels preventing action potentials from happening

How does BOTOX work to reduce wrinkles?

Causes hypoexcitability in muscles by cleaving SNAREs and prevents neurotransmitter release

  What damages does tetanus toxin cause?

a.     Lockjaw/mild spasms in jaw muscles, the spreads to chest, neck, back, and abdominal muscles, and sometimes respiration muscles

b.     Degrades part of v-SNARE disrupting the release of GABA and glycine

c.     Gives effect of hyperexcitability for postsynaptic neuron

How does Prozac work? What neurotransmitter is the target?

a.     Selective serotonin reuptake inhibitor (SSRI) blocks serotonin transporter (SERT) allowing serotonin signal to last longer

b.     Normally serotonin re-uptaken into presynaptic cell, but if blocked will stay at synaptic cleft for longer

c.     Side effect is altered homeostasis, serotonin production & secretion is decreased ["tolerance"]

What is the target and effect of cocaine and amphetamine?

Block reuptake of norepinephrine, dopamine, serotonin

What is the target and effect of cannabinoids?

a.     Retrograde signalling: endocannabinoid synthesized in postsynaptic cell and blocks Ca2+ channels in presynaptic cell, thus blocks neurotransmitter release

b.     THC agonist of cannabinoid receptors

For other toxins and drugs not commonly seen in the medical field, when given the cellular target, be able to figure out the effect

a.     Tetrodotoxin (TTX) blocks Na+ channel pore and prevents initiation and propagation of action potentials, causing hypoexcitability in neurons and muscle cells

b.     Sarin inhibits acetylcholinesterase, causing buildup of ACh in synaptic cleft, muscle contraction without relaxation resulting in death up to 10 minutes after direct inhalation due to suffocation as a result of loss of lung function

c.     Latrotoxins (LTXs) deplete ACh release in a Ca2+ independent manner at nmj, very strong contraction of the muscle

d.     Ecstasy (MDMA) blocks serotonin uptake, permanently damages neurons

e.     LSD is serotonin receptor agonist