Excitable cells often turn electrical
activity into what?
Ca2+-driven process mediated by voltage-sensitive Ca2+ channels.
What are connexons?
- Connexons are pair of hemichannels that makes up a gap junction.
- made up of 6 identical connexin subunits
- connexin: 7.5 nm long, has 4 membrane spanning regions
Current injected into the large presynaptic fiber produces an AP where?
in postysynaptic cell.
Most electrical synapses allow current flow in ______ across the synapse.
What are the 4 advantages of electrical synapses?
- 1. speed
- 2. coordinating activity in large groups of cells.
- 3. allow transfer of metabolites between cells.
- 4. gaps junctions can close in response to unfavorable conditions.
Where are gap junctions found?
in most multicellular tissues.
What is Charcot-Marie-Tooth?
A disease where connexin32 is defective. Demyelinating.
Connexin26 mutations in the epithelial cells of the inner ear lead to what?
What is oculodentodigital dysplasia?
Defective connexin43. Enamel hypoplasia, craniofacial anomalies and cardiac dysfunction.
Describe the significance of 1921 Otto Loewi experiment with the frog heart.
It proved that there is chemical transmission
What is the significance of the experiment in 1936 by Sir Henry Dale?
He found acetylcholine (ACh) was released by the motor nerve innervating skeletal muscle.
Describe the steps in chemical synaptic transmission.
- 1. Arrival of an action potential (AP) at presynaptic
- terminal leads to depolarization and opening of voltage-gated Ca2+ channels.
2. Ca2+ enters the presynaptic terminal. The Ca2+ concentration near active zone increases.
- 3. Ca2+ causes vesicles to fuse with the presynaptic
- membrane. Neurotransmitter (NT) is released into the synaptic cleft (exocytosis).
- 4. NT
- molecules diffuse across the synaptic cleft and bind to postsynaptic receptors.
- 5. Receptor
- binding leads to the opening of ion channels, a change in current flow through
- the post-synaptic cell and the generation of the post-synaptic potential.
What are receptors?
- Proteins that span the membrane. They have an extracellular site that recognizes and binds NT.
- Have an effector function: typically gate the opening or closing of ion channels (can excite or inhibit)
What is the difference between ionotropic and metabotropic receptors?
- ionotropic receptros: have direct effects on ion channels
- metabotropic receptors: have indirect, slower actions thru 2nd messenger systems
Describe the end plate.
- axon of the motor neuron loses its myelin sheath and divides into several branches
- ACh is released from small clear vesicles in the boutons into the junctional folds of the underlying postsynaptic muscle fiber.
What are the 3 types of neuro muscular junction proteins?
- 1. nicotinic ACh receptors: at the top of junctional folds at a density of about 10,000 receptors per micrometer2
- 2. Na+ channels: found at the base of the folds
- 3. Acetylcholinesterase: enzyme that causes the hydrolysis of ACh. Present in the synaptic cleft.
ACh diffuses and binds to the postsynaptic _____
receptor-channel complex after the ACh release.
What generates the end plate potential?
- The opening of ion channels allows the flow of Na+ and K ions across the postsynaptic membrane.
- The depolarization is usually large enough to open sodium channels and trigger an AP in the muscle.
What does curare do?
- Block the binding of ACh to receptors.
- the potential is largest at the end plate region and decays with distance along the muscle fiber.
What is the significance of the patch clamp technique was used on the 1976 Neher and Sakmann?
They recorded the opening and closing of single ACh - gated channels in muscle cells.
Nicotinic ACh receptor-channel requires ____ molecules of ACh to bind and change the conformation for sodium to come in.
What is alpha - bungarotoxin?
- Toxin from snake venom.
- binds irreversibly to alpha subunit and blocks the ACh receptor.
What is Botulinum Toxin?
- Neurotoxin produced by Clostridium botulinum bacteria.
- can be ingested or inhaled
- exists as toxin or spores
- causes muscle paralysis
- blocks release of ACh at the neuromuscular junction by clipping SNARE proteins
What is Myasthenia gravis and what happens biologically?
- it is an autoimmune disease
- antibodies are made to the neuromuscular ACh receptor
- Ab blocks the receptors which decreases the number of functional receptors
- results in muscle weakness
What are the symptoms of Myasthenia gravis?
- drooping eyelids (ptosis)
- double vision (diplopia)
- difficulty speaking (dysarthria)
- difficulty swallowing (dysphagia)
What is the treatment for Myasthenia gravia?
cholinesterase inhibitors inactivate acetylcholinesterase in the synaptic cleft and extend the life of ACh
Which is faster, electrical or chemical transmission?
Electrical is much faster.
Explain the difference in synapse structure of electrical vs. chemical transmission.
- Electrical synapse: cytoplasm is continuous with distance between pre/post is 3nm.
- chemical transmission: no cytoplasmic continuity, cleft is 20-40 nm wide.
Which transmission is bidirection and which is unidirectional? Which allows amplification?
- Bi-directional - electrical
- unidirectional: chemical
- amplification: chemical
What are the 4 criteria to be a neurotransmitter?
1. Synthesized in the neuron.
- 2. Present in presynaptic terminal, released in sufficient quantities
- to effect a change in postsynaptic/target structure.
- 3. Mimics action of endogenous substance when applied
- 4. Specific mechanism exists for removal from its site of
What are the 2 broad classes of neurotransmitters?
- 1. small molecule: rapidly acting transmitters. ex. ACh, glutamate
- 2. Neuroactive peptides: slowly acting transmitters. Ex. gastrin, angiotensin II
Describe the types of synaptic vesicles.
- 1. small: for glutamate, ACh, GABA
- 2. large: dense core vesicles
What is the co-release of the neurotransmitters? What about the adrenal medulla?
- the release of small molecule trasnmitter and neuropeptide are both released from a large, dense-core vesicle.
- Adrenal medulla contains secretory
- granules, similar to dense-core vesicles, epinephrine is released directly into
- the bloodstream.
each neuron must sum or _______ the information it receives and produce an output signal.
Synapses which are excitatory are often found on ______. Inhibitory synapses are often found on the _____.
What is axon hillock?
- The initial segment of the axon and the site of AP generation.
- Na+ channels are concentrated in the initial segment
- passive membrane properties will also affect the summation of synaptic inputs
Effectiveness of chemical synapses can be altered in the short term or long term by what 2 ways?
- a. changes within the neuron
- b. extrinsic factors : input from other cells
What is the most common excitatory transmitter in the central nervous system (CNS)?
What are the 3 types of ionotropic glutamate reeptors that mediate excitatory responses?
- AMPA : blocked by CNQX
- Kainate : blocked by CNQX
- NMDA : blocked by APV
What does the metabotropic glutamate receptors do?
- Mediate excitatory or inhibitory response.
- the binding to this receptor stimulates PLC leading to formation of 2nd messengers DAG and IP3.
- activated by amino cyclopentadicarboxylic acid (ACPD)
Which receptors involve in the early part of the excitatory post-synaptic potential (EPSP) and which involves in the late phase?
- Early part of EPSP: AMPA/kainate
- Late part of EPSP: NMDA
What are the 3 unusual features of the NMDA receptor?
- 1. High conductance channel opened by NMDA is permeable to Ca2+ as well as Na+ and K+.
- 2. Glycine required as cofactor for channel opening.
- 3. at hyperpolarized potentials Mg2+ blocks the channel. At the cell's resting potential, Mg2+ enters the receptor-channel and binds tightly. Following a depolarization, Mg2+ is ejected from channel allowing Na+ and Ca2+ to enter cell.
NMDA is _____ current. AMPA is _____ current.
what happens when presynaptic neuron fires repeatedly?
- EPSP will summate => larger depolarization => more Ca2+ will eneter the cell => triggers Ca2+ dependent processes
- this process is thought to be involved in learning and memory
What is spatial summation?
when 2 or more presynaptic inputs arrive at the same time at the postsynaptic cell and act at different sites
What is temporal summation?
when 2 or more consecutive presynaptic inputs at the same site are added together in the postsynaptic cell.
What is excitotoxicity?
- Too much glutamate = toxic
- excess Ca2+ to enter through the NMDA receptor
- lead to stroke, seizures, neurodegeneration and cell death
Which type of receptor mediate inhibitory transmission?
Describe the function of GABAA receptor.
- ionotropic receptor that gates the Cl channel
- ECl = -90 mV
- cell's resting potential is more positive than that
- net influx of Cl
- leads to hyperpolarization (inhibition)
What is GABAB?
- metabotropic receptor
- activates K+ channels
- outwards K current results in hyperpolarization
- Ca2+ channels may be inhibited via 2nd messenger pathway
What does glycine do?
- activates ionotropic receptors that open Cl channels
- strychnine and tetanus toxin block glycine receptors
- when glycine is blocked, muscle spasms occur => opisthotonos
What is the structure of GABAA receptor?
- composed of 5 subunits
- 2 alpha, 2 beta, 1 gamma
- subunits are similar and GABA can bind any one
What is the glycine receptor?
- 3 alpha and 2 beta subunits
- glycine binds to the alpha subunits
What is benzodiazepines?
- is a drug that bind to the gamma subunit of the GABAA channel
- increase Cl conductance thru the channel
alcohol and barbiturates ______ the effect of GABA.