contents

  • action potentials transmit a message from one end of a cell (neuron) to the other
  • messages need to be transmitted between cells across the synapse
  • an analogy would be:
    • breathing in air before talking: action potential
    • making the sounds to communicate: neurotransmitters
  • neurons talk to each other using the language of neurotransmitters
    • neurotransmitters are a list of molecules
  • neurotransmitters have several functions in the body
    • one of their dedicated functions is inter-neuron communication
  • neurotransmitters are made in the nervous system and are released from synaptic terminals

neurotransmitter synthesis

neuron-anatomy

fig: neuron anatomy

  • cell organelles include:
    • nucleus: has the DNA
    • mitochondria: powerhouse of the cell
    • endoplasmic reticulum: cell protein manufacturing centers
    • endosomes and lysosomes: garbage collectors of the cell
    • axon: leads to the synaptic terminal

synaptic terminal

  • the synaptic terminal has synaptic vesicles
    • these are organelles with a vesicular membrane
    • inside a membrane sit neurotransmitter molecules

neuron-anatomy

fig: synaptic terminal anatomy

neurotransmitter molecules

  • neurotransmitters may be any of the following molecules
    • acetylcholine
    • glutamate
    • GABA (gamma-aminobutyric acid)
    • glycine
    • dopamine
    • norepinephrine
    • epinephrine
    • histamine
    • serotonin
    • ATP (adenosine tri-phosphate)
    • enkephalin
    • beta-endorphin
    • dynorphin
    • vasopressin
    • oxytocin
    • insulin
    • galanin
    • nitric oxide
    • substance P
    • calcitonin gene-related protein (CGRP)
    • bombesin
    • kisspeptin
    • 100+ more
  • synthesis of neurotransmitters may be used as a therapeutic tool
    • eg. in parkinson’s disease, dopamine making cell groups die
    • substrate subjected to a series of enzymatic reactions generate neurotransmitters
    • to treat parkinson’s disease, the substrate in drugs sinemet (aka parcopa) is used
      • dopamine is synthesized in patient’s system when flooded with said substrate
  • neurotransmitters are packaged in vesicles
    • these packages are neural communication units

neurotransmitter release

  • the cell has a lot of membranes
    • all the cell organelles have membranes
  • other vesicles traffic through the membranes to their target locations
    • the fusion between the membranes of vesicle and the target organelle membrane happens all the time to enable this traffic
  • however, neuron vesicles should not fuse with the neuron cell membrane all the time
    • neuron vesicle fusion should occur only in the event of an action potential
    • if it took place all the time, neuron communication and hence bodily regulation would fail

key to neurotransmitter release

  • suppress constitutive (always active) release
    • at the synaptic terminal
  • link release to action potential

release process

  • action potential travels down the axon
  • neurotransmitters packaged in vesicles are held ready in the synapse
  • when the action potential occurs, the potential across the cell membrane skyrockets
    • this begins opening up ion channels
    • this lets in \(Ca^{++}\) ions into the synaptic terminal through the opened ion channels
    • the influx of calcium ions triggers the neurotransmitter release
    • by enabling the fusion of vesicle and neuron cell membrane fusion

release trigger

  • vesicles of neurotransmitters are released only when \(Ca^{++}\) ions flood the synaptic terminal
    • this occurs only when the ions channels are opened in the neuron cell membrane by its own action potential event

cell-vesicle-membrane-fusion

fig: cell membrane and vesicle membrane fusion

  • in the presence of \(Ca^{++}\), the vesicle membrane fuses with the neuron cell membrane internally to open up the inner neurotransmitter molecules into the synaptic gap

cell-vesicle-membrane-fusion

fig: vesicle membrane patches the hole in the cell membrane

  • then the vesicle membrane closes the hole created in the cell membrane to release the molecules, after the release
  • so, the act of releasing the neurotransmitters is not pumping it out to the target
    • the molecules are simply ejected out of the neuron body
    • the hole created in the neuron membrane is then closed with the vesicle membrane that held the neurotransmitters packed together to begin with

clostridial toxins - botox

  • botox is one of the several clostridial toxins made by the clostridial bacteria
  • botox stands for botulinum toxin

snare complex

  • three proteins hold vesicles close to the cell membrane
    • one is anchored in the vesicle membrane
    • other two anchored in the cell membrane
    • these are also called pin proteins
  • when \(Ca^{++}\) ions enters the synaptic terminal
    • it forces shape change of the snare complex
    • this forces the vesicle membrane into the cell membrane
    • makes the fusion of the vesicle with cell membrane inevitable

botox action

  • clostridial toxin cuts the proteins of the snare molecules
    • this prevents neurotransmitter release
  • particular case
    • prevents release of neurotransmitter from motor-neurons
malicious use
  • release from motor neuron to diaphragm is an area of concern
    • for a patient administered with a sufficient amount of botox
    • diaphragm is a muscle that facilitates breathing
  • botox (a bio-toxin) may be used as a weapon (of mass destruction) to clog human diaphragms
    • the dosage matters
therapeutic use
  • focal dystonia:
    • there is a continual contraction of a muscle stemming from a basal ganglia disorder
    • botox, in low and very local dosage, is injected to treat focal dystonia
      • it blocks the disorder enforced contraction of the muscle
  • cosmetic applications:
    • botox prevents motor neuron from releasing neurotransmitter to muscles
    • this prevents wrinkle generation

signal termination

  • release happens to get a message across the synaptic cleft
    • from pre-synaptic cell (the synaptic terminal releasing the neurotransmitter)
    • to post-synaptic cell
  • synaptic cleft is a short distance separation between the communicating cells
    • molecules released into the synaptic cleft are about to be received
  • the message needs to be terminated
    • there three different mechanisms for message termination

diffusion

  • the post-synaptic cell is sensitive with receptors for released molecules only in a certain area
  • this means that diffusion is a natural process that ends the communication
    • as the released molecules diffuse out of the receiving cell’s sensitive area

re-uptake

  • transporters of the pre-synaptic cell take un-communicated neurotransmitters in the synaptic cleft back in
  • neurons recycle neurotransmitters
    • the neurotransmitters taken back in are repackaged in vesicles
    • released again at action potentials
  • re-uptake is crucial for drugs like serotonin and dopamine to work
    • as a result, re-uptake mechanism may be used treat depression
  • re-uptake may also engage circuits that lead to drug abuse

degradation

  • enzymes in the synaptic cleft eat up the leftover neurotransmitters

  • eg: acetylcholine neurotransmitter is eaten up by AChE (acetylcholinesterase)
    • acetylcholine is used by motor neurons
  • myasthenia gravis:
    • not enough acetylcholine is released, or receptors for it are less
    • in this case, action of AChE (acetylcholinesterase) is inhibited
    • to prevent acetylcholinesterase from eaten up the existing acetylcholine
  • pesticides such as ceron are based on blocking the AChE
    • acetylcholine is not eaten up by AChE
    • this leaves to much acetylcholine for the post-synaptic cell
    • too much acetylcholine in a post-synaptic motor neuron make it actuate the muscle to stay contracted continuously
    • in case this is the diaphragm, it leads to death
      • because the diaphragm stays locked

receptors

  • the post-synaptic cell has to receive the message
  • receptors populate the post-synaptic cell membrane
    • receptors are multi-protein complexes
  • as the neurotransmitter molecules make their way across the cleft
    • the surviving molecules reach the receptors

structure

  • post-synaptic membrane has actual pores
    • normally they are closed
  • ion can go in and out of the membrane through these pores
    • \(K^+\) travels out of the cell
    • \(Na^+\) and \(Cl^-\) travel into the cell
  • when receptors bind to the receptors
    • pores become available for the ions to travel along
      • ionotropic receptors: open ion channels (open pores)
      • pore opens in \( < ms \)
    • direction of travel depends on the receptor
  • there are about 10 types of ionotropic receptors
  • knee jerk reflex type effect

classes of receptors

excitatory receptors
  • any receptor that takes the cell membrane voltage higher, closer to \(0V\)
  • eg:
    • glutamate receptor
    • glutamate neurotransmitter binds to this receptor
  • makes action potential firing more likely
inhibitory receptor
  • any receptor that takes the cell membrane voltage lower than it default \(-65mV\)
  • eg:
    • GABA receptor
    • GABA neurotransmitter binds to this receptor
  • makes action potential firing less likely

flow of communication

  • the pre-synaptic and the post-synaptic cells action potentials must fire in succession with appropriate overlap
    • this enable flow of neurotransmitters from the pre-synaptic to post-synaptic cell
    • across the synaptic cleft
    • where the neurotransmitter ejected by the pre-synaptic cell collect on the post-synaptic receptors
    • this opens pores for ions to enter or exit the post-synaptic cell

disease and therapeutics

  • diseases receptors are lost: myasthenia gravis

  • consider human motor-neuron synaptic terminal and muscle interface
    • synaptic vesicles contain ACh (acetylcholine neurotransmitter)
    • acetylcholine neurotransmitter contracts muscles
    • muscle membrane has acetylcholine receptors
  • in myasthenia gravis, the immune system antibodies made in the body destroys a whole lot of the acetylcholine receptors of the muscle cells
  • to counter this condition, the inhibitor (acetylcholinesterase) that eats away acetylcholine in the synaptic cleft is blocked
    • so, more acetylcholine floods the cleft, as it is kept around longer and not degraded by its inhibitor
    • the probability of it binding with a receptor increases
    • this situation is better than having a low receptor count and low concentration of acetylcholine
  • another counter is to suppress the immune system nad its antibodies from destroying the acetylcholine receptors

metabotropic receptors

  • they bind neurotransmitters, but do not directly lead to an electric change
    • they cannot form a pore
    • they activate G protein by attaching with them
    • so, they are also called G protein coupled receptors (GPCR)
  • activated G protein stimulate enzymatic reactions
    • or bind to other molecules which inturn stimulate enzymatic reactions
  • the effect of metabotropic receptors take more time than ionotropic receptors
    • in the order of \(mS\)
    • their effect amplifies
    • goes on in many rounds
    • their effect is difficult to turn off
  • the effect could be to open, close or not affect ion channels at all
    • huge variations in effect
  • there are more than a 1000 types of metabotropic receptors

  • adrenaline rush type effect

  • all autonomic target organs use metabotropic receptors
    • drugs used to treat glaucoma, hypertension, motion sickness, asthma, IBS
    • all act on GPCRs
    • GPCRs are a common target for drug development
most commonly prescribed drug
  • in the u.s.a, most commonly prescribed drug is vicodin
    • mix of hydrocodone and acetaminophen
    • hydrocodone, the active ingredient in vicodin, acts on GPCR called the mu-opiod receptor

disconnect

  • consider myelin sheath, a part of neuro-anatomy
  • even if we knew everything about how myelin works
    • it would not tell us what happens if myelin fails
  • it depends on what is affected because of the failure of myelin
    • the neurons functions that are affected by myelin failure
  • the context in the complex neuro-anatomy system is important to analyze the effects of failure
    • for this understanding the system as a whole is crucial

reference