Transcript NEUROCHEMISTRY & NEUROTRANSMITTERS

NEUROCHEMISTRY &
NEUROTRANSMITTERS
NEUROCHEMISTRY IS A SUB-SPECIALTY OF
BIOCHEMISTRY THAT DEVELOPED RAPIDLY
IN THE 1950’S. IT DEALS PRIMARILY WITH THE
CHEMISTRY OF THE BRAIN AND NERVOUS
SYSTEM.
A VERY IMPORTANT PART OF
THIS DISCIPLINE DEALS WITH
SO-CALLED “NEUROTRANSMITTER SUBSTANCES” WHICH ARE
SIGNALING CHEMICALS SENT
BETWEEN NERVE & NERVE AND
NERVE & MUSCLE. THESE
SUBSTANCES ARE CLOSELY
RELATED TO HORMONES.
OTTO LOEWI
ANOTHER WAY OF LOOKING AT HORMONES, NEUROTRANMITTERS
AND RELATED MOLECULES IS SIMPLY TO LABEL THEM AS SIGNALLING
DEVICES, BUT THAT IS A BIT OF AN OVERSIMPLIFICATION.
OUTLINE:
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REVIEW OF NERVOUS SYSTEM; TRANSMISSION
GATED PROTEINS OF NERVOUS TRANSMISSION
THE PRESYNAPTIC AREA OF NEURONS
NEUROTRANSMITTERS & SYNTHESIS
THE SYNAPTIC AND POSTSYNAPTIC AREAS
RECEPTOR PROTEINS
SURVEY OF NEUROTRANSMITTER DISEASES
THIS IS AN INTRODUCTION TO NEUROLOGY
& PHARMACOLOGY.
WHAT DO WE REMEMBER FROM UNDERGRADUATE STUDIES ABOUT
COMPONENTS & FUNCTIONS OF THE NERVOUS SYSTEM?
(REVIEW OF THE NERVOUS SYSTEM & NEUROTRANSMISSION)
NERVE (aka NEURON)
IS A CELL TYPE THAT COMMUNICATES
INFORMATION BY ELECTRICAL AND CHEMICAL
MEANS. THE INFORMATION, TYPICALLY (BUT
WITH EXCEPTIONS), TRAVELS FROM THE
DENDRITE THROUGH THE CELL BODY AND
THE AXON TO THE AXON TERMINALS.
JUST LIKE HORMONES, THE COMMUNICATION
(OR SIGNALLING) IS MEANT TO COORDINATE THE
ACTIONS OF HIGHER ORGANISMS, BUT IN A MUCH
MORE RAPID MANNER THAN IS COMMON TO
HORMONES. TYPICALLY THE RATE OF NERVE
CONDUCTION TAKES PLACE AT 1 TO 100 meters/
second FOR UNMYELINATED NERVES [WE’LL
TAKE UP THE SUBJECT OF MYELINATION A LITTLE
LATER]. THE RATE OF CONDUCTION ALSO
INCREASES WITH THE DIAMETER OF THE NEURON
ITSELF.
1) NEURONS
SERVE THE CNS
2) SEVERAL KINDS
ARE REQUIRED
IN ORDER TO OPERATE
THE COMPLETE
NERVOUS SYSTEM,
OTHER NEURON TYPES
ARE NECESSARY –
SUCH AS MOTOR &
SENSORY NEURONS.
WHILE THE MOTOR
NEURON SENDS SIGNALS
TO MUSCLES, THE
SENSORY NEURON
TRANSDUCES SIGNALS
SUCH AS HEAT AND PAIN
INTO SIGNALS AND SENDS
THEM TO THE BRAIN.
THE IMPORTANT
DIFFERENCE IN THESE
NERVES IS THE PRESENCE
OF MYELINATION.
THE CONDUCTION PROPERTIES
OF NERVES IN AN UNMYELINATED NERVE, AT REST,
THE POTENTIAL ACROSS THE NERVE
MEMBRANE IS ~ -60mV. WHEN A WAVE
OF DEPOLARIZATION TRAVELS DOWN
THE NERVE, THE NERVE POTENIAL
INCREASES TO ~ +30mV, THEN RAPIDLY
HYPERPOLARIZES BEFORE RETURNING
TO THE RESTING POTENTIAL IN ABOUT
3.8 msec.
THIS IS ACCOMPANIED BY TWO
EVENTS AT THE NEURAL MEMBRANE,
1st AN INCREASE IN Na ion
PERMEABILITY, THEN AN INCREASE IN
K ion PERMEABILITY.
WHAT CAUSES THESE EVENTS?
REMEMBER THAT, NORMALLY, POTASSIUM IS HIGHER IN CONCENTRATIION
INSIDE THE CELL WHILE SODIUM IS HIGHER OUTSIDE THE CELL. ANY
CHANGE IN MEMBRANE PERMEABILITY SPECIFIC FOR THESE IONS WILL
CAUSE THEM TO FLOW INWARD FOR SODIUM – OUTWARD FOR POTASSIUM.
IF SODIUM IS ALLOWED TO FLOW INWARD, THE POTENTIAL BECOMES
MORE POSITIVE. IF POTASSIUM IS ALLOWED TO FLOW OUTWARD,
THE POTENTIAL BECOMES MORE NEGATIVE. THE FLOW IS CONTROLLED
BY “GATED” ION CHANNEL PROTEINS. THESE MEMBRANE PROTEINS ARE
AFFECTED BY LOCAL VARIATIONS IN ION CONCENTRATION AND POTENTIAL.
SODIUM CHANNEL
PROTEIN
= -60mV (negative inside)
THE STRUCTURE AND OPERATION OF THE POTASSIUM GATED CHANNEL
PROTEIN IS SIMILAR TO THAT OF THE SODIUM GATED CHANNEL PROTEIN
WITH SOME ESSENTIAL DIFFERENCES:
1) THERE IS A MOLECULAR FILTER THAT PREVENTS THE PASSAGE OF
SMALLER SODIUM IONS THROUGH THE CHANNEL. WHY IS SUCH A
FILTER NOT NECESSARY FOR SODIUM GATED CHANNEL PROTEINS?
2) THE OPENING OF THE POTASSIUM GATED CHANNEL IS DELAYED IN
TIME BY THE LOCAL VOLTAGE CHANGES SO THAT: AS THE POTASSIUM
CHANNEL STARTS TO OPEN, THE SODIUM CHANNEL STARTS TO CLOSE.
SODIUM CHANNEL TOXINS:
TETRODOTOXIN
(puffer fish) AND SAXITOXIN (plankton species)
BIND WITH HIGH SPECIFICITY TO SODIUM
CHANNELS (KD = <1 nM). THESE ARE USED
IN RADIOACTIVE FORMS TO PURIFY SODIUM
CHANNEL PROTEINS AND MAP THEIR
LOCATIONS ON AXONS. SAXITOXIN IS FOUND
IN SOME FORMS OF THE “RED TIDE” FAMILIAR
TO PEOPLE WHO LIVE ALONG SEA COASTS.
SAXITOXIN
LOOKING AT THE ACTION
POTENTIAL IN MOTION:
THIS SHOWS HOW THE
ACTION POTENTIAL
MOVES ALONG THE
AXON WITH TIME. THE
OPENING AND CLOSING
OF GATED CHANNEL
PROTEINS IS ONLY
SHOWN FOR Na+ IONS
FOR SIMPLICITY.
TIME = 0
TIME = 1 ms
HYPERPOLARIZATIOIN
GUARANTEES THAT THE
WAVE OF DEPOLARIZATION
IS UNIDIRECTIONAL. AT TIME
= 0 (e. g., WHEN ACTIVATED
BY A STIMULUS) A GIVEN
AREA (DISTANCE) OF
MEMBRANE IS IMMEDIATELY
DEPOLARIZED.
TIME = 2 ms
MYELINATION: WHAT IS IT AND WHAT DOES IT DO?
MYELINATION IS THE ADDITION OF CONCENTRIC PLASMA MEMBRANES
AROUND THE REGULAR PLASMA MEMBRANE OF A NEURON. THE MYELIN
IS PRODUCED BY A GLIAL CELL KNOWN AS A SCHWANN CELL.
MYELIN
SHEATH
MYELIN
LAYERS
NODES OF
RANVIER
AXON
NOTE THAT THE
SHEATHS ARE
SCHWANN
SEPARATED BY
CELL
SHORT NON-MYELINATED SPACES.
THE COMPOSITION OF THE MYELIN LAYERS IS
SIMILAR IN LIPID TYPES TO THOSE OF THE PLASMA
MEMBRANE. HOWEVER, 2 PROTEINS ARE UNIQUE
TO THE MEMBRANE: (PO IN THE PNS) AND PROTEOLIPID (IN THE CNS).
THE ROLE OF THESE PROTEINS IS TO BIND TO THEMSELVES AND HOLD
THE LAYERS TOGETHER.
MYELINATED NERVES HAVE THE ADVANTAGE OF ALLOWING CONDUCTION
TO OCCUR AT 10x THE RATE OF UNMYELINATED NERVES. THIS IS VERY
IMPORTANT FOR COMMUNICATING WITH MUSCLES (FROM THE CNS) AND
SIGNALLING THE RECEPTION OF PERIPHERAL PAIN, PRESSURE, ETC. (TO
THE CNS).
SINCE THE VELOCITY OF NERVE CONDUCTION IS PROPORTIONAL TO
NERVE CROSS SECTION, IT ALSO MYELINATED NERVES ALLOW THE
EXISTENCE OF THINNER NERVES. FOR EXAMPLE, A 12 mm DIAMETER
MYELINATED NERVE WILL CONDUCT AT A RATE OF 12 m/s. THE
COMPARABLE CONDUCTING UNMYELINATED NERVE MUST BE 600 mm IN
DIAMETER.
IN PRACTICAL TERMS, WE
WOULD HAVE TO HAVE SPINAL
CHORDS AS THICK AS TREE TRUNKS
TO CARRY OUT OUR NORMAL,
HUMAN NEUROLOGICAL FUNCTIONS!
myelinated
unmyelinated
HOW MYELINATED NEURONS WORK:
MYELINATED NEURONS CONDUCT BY THE PROCESS OF SALTATORY
(LATIN – SALTARE “TO JUMP”) DEPOLARIZATION. IN THE MYELINATED
NEURON, NEARLY ALL OF THE SODIUM ION GATED CHANNEL PROTEINS
ARE LOCATED AT THE NODES OF RANVIER. CONSEQUENTLY, DEPOLARIZATION OCCURS AT THE NODES AND JUMPS FROM NODE TO NODE AT
A HIGHER RATE THAN SIMPLE DEPOLARIZATION ON AN UNMYELINATED
NERVE.
a) CONCENTRATED VOLTAGE
GATED Na+ CHANNELS
DEPOLARIZE A LOCAL AREA.
b) DEPOLARIZATION MOVES
RAPIDLY DOWN THE INSIDE
OF THE AXON (JUMPS) TO
THE NEXT NODE.
c) AT THE NEXT NODE, THE
CHANNELS OPEN AND
CAUSE THE NEXT WAVE OF
DEPOLARIZATION.
THE PRESYNAPTIC AREA
WITH THE ARRIVAL OF THE DEPOLARIZED SIGNAL AT THE PRESYNAPTIC
AREA A NUMBER OF EVENTS OCCUR THAT MUST BE CONSIDERED
SEPARATELY AND TOGETHER :
1) THE TRANSDUCTION OF THE SIGNAL IN THIS AREA
2) THE SYNTHESIS OF NEUROTRANSMITTERS
3) THE MECHANISM(S) OF TRANSMITTER RELEASE
4) THE KINDS OF NEUROTRANSMITTERS THAT EXIST
5) HOW A SUBSTANCE CAN “QUALIFY” AS A NEUROTRANSMITTER
6) THE SEQUENCE OF EVENTS THAT CAUSE TRANSMITTER RELEASE
ARRIVAL AT THE SYNAPSE
WITH THE ARRIVAL OF THE DEPOLARIZED SIGNAL AT THE SYNAPSE
A NUMBER OF EVENTS OCCUR THAT MUST BE CONSIDERED SEPARATELY
AND TOGETHER :
1)THE TRANSDUCTION OF THE SIGNAL
2) THE SYNTHESIS OF NEUROTRANSMITTERS
3) THE MECHANISM(S) OF TRANSMITTER RELEASE
4) THE KINDS OF NEUROTRANSMITTERS THAT EXIST
5) HOW A SUBSTANCE CAN “QUALIFY” AS A NEUROTRANSMITTER
6) THE SEQUENCE OF EVENTS THAT CAUSE TRANSMITTER RELEASE
THE PRESYNAPTIC AREA (aka AXON TERMINAL) IS A VERY BUSY LOCATION.
THE ELECTRON MICROGRAPH SHOWS THE PRESENCE OF MANY VESICLES
AND FIBERS. THE AREA IS TYPICALLY WIDER THAN THE AXON TO FACILITATE
RAPID COMMUNICATION WITH THE POSTSYNAPTIC CELL.
WHEN THE WAVE OF DEPOLARZATION ARRIVES AT THIS AREA,
Ca+2 IONS PLAY AN IMPORTANT
DOUBLE ROLE IN THE
TRANSDUCTION OF THE SIGNAL
THAT CAUSESTHE RELEASE OF
NEUROTRANSMITTERS.
DEPOLARIZATION AT THIS POINT
CAUSES THE OPENING OF
VOLTAGE GATED Ca+2 CHANNEL
PROTEINS.
THE FIGURE SHOWS TWO STAGES
OF THE ROLE OF Ca+2 IN THIS
PROCESS.
A) THE Ca+2 CHANNEL PROTEIN
(GREEN) IS CLOSED WITH
HIGHER CONCENTRATIONS OF
Ca+2 IN THE SYNAPTIC CLEFT.
B) UPON DEPOLARIZATION, THE
CHANNEL PROTEIN OPENS AND
ADMITS Ca+2 (RED DOTS) TO THE
PRESYNAPTIC CYTOPLASM. THIS
CAUSES: 1. TRANSPORT OF THE
SYNAPTIC VESICLE TO THE
SYNAPTIC MEMBRANE, FUSION &
2. OPENING OF THE SYNAPTIC
VESICLE TO THE SYNAPTIC CLEFT.
NOTE: A NUMBER OF PRESYNAPTIC
PROTEINS ARE INVOLVED IN
THIS TRANSPORT AND FUSION
PROCESS.
SYNAPTIC CLEFT
SYNAPTIC CLEFT
ARRIVAL AT THE SYNAPSE
WITH THE ARRIVAL OF THE DEPOLARIZED SIGNAL AT THE SYNAPSE
A NUMBER OF EVENTS OCCUR THAT MUST BE CONSIDERED SEPARATELY
AND TOGETHER :
1) THE TRANSDUCTION OF THE SIGNAL
2)THE SYNTHESIS OF NEUROTRANSMITTERS
3) THE MECHANISM(S) OF TRANSMITTER RELEASE
4) THE KINDS OF NEUROTRANSMITTERS THAT EXIST
5) HOW A SUBSTANCE CAN “QUALIFY” AS A NEUROTRANSMITTER
6) THE SEQUENCE OF EVENTS THAT CAUSE TRANSMITTER RELEASE
THE SYNTHESIS OF NEUROTRANSMITTERS AND THEIR STORAGE TAKES
PLACE IN THE PRESYNAPSE. EVEN THOUGH WE HAVE NOT YET
CONSIDERED NEUROTRANSMITTERS -- EXCEPT TO SAY THAT THEY
ARE BIOCHEMICALS THAT CONVEY SIGNALS FROM NEURON TO NEURON
OR NEURON TO MUSCLE – LET’S LOOK AT THE SYNTHESIS OF TWO
COMMON NEUROTRANSMITTERS: ACETYLCHOLINE AND NOREPINEPHRINE.
ACETYLCHOLINE IS MADE FROM ACETYL-CoA AND CHOLINE (DIETARY
SOURCE):
THE SYNTHESIS IS ENTIRELY WITHIN THE PRESYNAPTIC CYTOPLASM.
BELOW YOU SEE THE DIAGRAM OF SYNTHESIS AND STORAGE
OF ACETYLCHOLINE
NOTE: THE REUSE
OF THE SYNTHETIC
BIOCHEMICALS –
ACETYL CoA AND
CHOLINE.
AFTER SYNTHESIS, THE
NEUROTRANSMITER
IS TAKEN UP INTO THE
PRESYNAPTIC VESICLE
AND THE VESICLE IS
USUALLY TAKEN TO THE
VICINITY OF THE
PRESYNAPTIC TERMINAL
(OR MEMBRANE). EACH
VESICLE CONTAINS ABOUT
10,000 ACETYLHOLINE (Ach)
MOLECULES.
THE SYNTHESIS OF NEUROEPINEPHRINE
IS MORE COMPLEX.
NOTE THE FOLLOWING:
1. THE SYNTHESIS MAY CONTINUE ON TO
EPINEPRINE. IT BEGINS WITH TYR.
2. NOREPINEPHRINE IS USUALLY A NT
WHILE EPINEPHRINE IS A HORMONE –
THE ROLES MAY BE REVERSED.
3. TYROSINE HYDROXYLASE IS THE
RATE LIMITING ENZYME.
4. AROMATIC AMINO ACID DECARBOXYLASE
IS AN ENZYME IN THE PATHWAY OF OTHER
NT SYNTHESES (PINK SQUARE).
5. DOPAMINE IS FORMED IN THE CYTOPLASM
AND THEN ENTERS THE VESICLES FOR THE
FINAL REACTION(S).
*DOPA = 3,4-DIHYDROXYPHENYLALANINE.
*
ARRIVAL AT THE SYNAPSE
WITH THE ARRIVAL OF THE DEPOLARIZED SIGNAL AT THE SYNAPSE
A NUMBER OF EVENTS OCCUR THAT MUST BE CONSIDERED SEPARATELY
AND TOGETHER :
1) THE TRANSDUCTION OF THE SIGNAL
2) THE SYNTHESIS OF NEUROTRANSMITTERS
3) THE MECHANISM(S) OF TRANSMITTER RELEASE
4) THE KINDS OF NEUROTRANSMITTERS THAT EXIST
5) HOW A SUBSTANCE CAN “QUALIFY” AS A NEUROTRANSMITTER
6) THE SEQUENCE OF EVENTS THAT CAUSE TRANSMITTER RELEASE
SO FAR WE KNOW THAT Ca+2 IONS INDUCE THE TRANSPORT AND FUSION
OF VESICLES CONTAINING NEUROTRANSMITTERS TO THE PRESYNAPTIC
MEMBRANE THAT BORDERS THE SYNAPSE.
WHAT HAPPENS NEXT?
A REFERENCE WAS MADE TO PROTEINS THAT ARE PROMPTED BY
Ca+2 IONS TO CAUSE FUSION OF VESICLES & PRE-SYN. MEMBRANES.
THIS IS ACCOMPLISHED WITH A PROTEIN COMPLEX OF SYNTAXINSYNAPTOBREVIN-SNAP25 MOLECULES. THESE MOLECULES HAVE
BEEN PROPOSED TO ALSO CONTINUE IN THE FORMATION OF PORES
IN THE FUSED MEMBRANES EITHER BY “FULL COLLAPSE” OR “KISSAND-RUN” MECHANISMS. THE FULL COLLAPSE MECHANISM CAUSES
THE COMPLETE EMPTYING OUT OF THE NTs IN THE VESICLE. THE
KISS AND RUN MECHANISM FORMS A TRANSIENT HOLE AND THEN
CLOSES LEAVING SOME OF THE NTs IN THE VESICLE. THE VARIATION
ALLOWS FOR CONTROL IN THE AMOUNT OF NT RELEASED INTO THE
SYNAPTIC CLEFT.
SNAP-25
SYNTAXIN
SYNAPTOBREVIN
PROTEIN COMPLEX AT THE
FUSED MEMBRANES FORCING
THE MEMBRANES OPEN AS A
RESULT OF Ca+2 BINDING.
SNAP = Synaptosome associated protein
is Ca+2 ion sensitive (25kD)
SYNTAXIN = 35 kD
SYNAPTOBREVIN = ~19 kD
ARRIVAL AT THE SYNAPSE
WITH THE ARRIVAL OF THE DEPOLARIZED SIGNAL AT THE SYNAPSE
A NUMBER OF EVENTS OCCUR THAT MUST BE CONSIDERED SEPARATELY
AND TOGETHER :
1) THE TRANSDUCTION OF THE SIGNAL
2) THE SYNTHESIS OF NEUROTRANSMITTERS
3) THE MECHANISM(S) OF TRANSMITTER RELEASE
4) THE KINDS OF NEUROTRANSMITTERS THAT EXIST
5) HOW A SUBSTANCE CAN “QUALIFY” AS A NEUROTRANSMITTER
6) THE SEQUENCE OF EVENTS THAT CAUSE TRANSMITTER RELEASE
NEUROTRANSMITTER S ARE
RELATIVELY SIMPLE, SMALL
MOLECULES
NOTE THAT ONE END OF THE
MOLECULE HAS A POSITIVE CHARGE
PARTIAL LIST:
CHOLINERGIC – e. g., ACETYLCHOLINE
CATECHOLAMINES – e. g., NOREPINEPHRINE
AMINO ACID/DERIVATIVES – e. g. GLYCINE,
g-AMINOBUTYRIC ACID
SOME HORMONES- e.g., EPINEPHRINE
NEUROMODULATORS- e.g. ENDORPHINS (NOT TRUE NTs)
ARRIVAL AT THE SYNAPSE
WITH THE ARRIVAL OF THE DEPOLARIZED SIGNAL AT THE SYNAPSE
A NUMBER OF EVENTS OCCUR THAT MUST BE CONSIDERED SEPARATELY
AND TOGETHER :
1) THE TRANSDUCTION OF THE SIGNAL
2) THE SYNTHESIS OF NEUROTRANSMITTERS
3) THE MECHANISM(S) OF TRANSMITTER RELEASE
4) THE KINDS OF NEUROTRANSMITTERS THAT EXIST
5) HOW A SUBSTANCE CAN “QUALIFY” AS A NEUROTRANSMITTER
6) THE SEQUENCE OF EVENTS THAT CAUSE TRANSMITTER RELEASE
THIS IS A GENERAL LIST THAT INVESTIGATORS HAVE COME TO
AGREE UPON FOR A SUBSTANCE TO BE CONSIDERED AS A
NEUROTRANSMITTER:
1) SUBSTANCE MUST BE PRESENT IN THE PRESYNAPSE.
2) SUBSTANCE MUST BE RELEASED WITH NEURAL STIMULATION.
3) EFFECTS OF SUBSTANCE, WHEN APPLIED TO A POSTSYNAPTIC
AREA, MUST BE IDENTICAL TO THE PHYSIOLOGICAL EVENT
CAUSED BY THE PRESYNAPTIC DEPOLARIZATION.
4) THE EFFECTS MUST BE PHYSIOLOGICALLY PROPORTIONAL TO
THE PRESYNAPTIC STIMULUS.
5) THERE MUST BE A LOCAL MECHANISM TO INACTIVATE THE
SUBSTANCE.
EXPERIMENTALLY SOME OF THESE CONDITIONS ARE DIFFICULT TO
OBTAIN DATA FOR.
ARRIVAL AT THE SYNAPSE
WITH THE ARRIVAL OF THE DEPOLARIZED SIGNAL AT THE SYNAPSE
A NUMBER OF EVENTS OCCUR THAT MUST BE CONSIDERED SEPARATELY
AND TOGETHER :
1) THE TRANSDUCTION OF THE SIGNAL
2) THE SYNTHESIS OF NEUROTRANSMITTERS
3) THE MECHANISM(S) OF TRANSMITTER RELEASE
4) THE KINDS OF NEUROTRANSMITTERS THAT EXIST
5) HOW A SUBSTANCE CAN “QUALIFY” AS A NEUROTRANSMITTER
6) THE SEQUENCE OF EVENTS THAT CAUSE TRANSMITTER RELEASE
A QUICK REVIEW AND LEAD IN TO WHAT OCCURS AT THE POSTSYNAPSE
WHAT WE NOW WANT TO COVER ARE A FEW DETAILS ABOUT THE
SYNAPSE, RECEPTORS AND INACTIVATION
THE SYNAPTIC CLEFT
THE SYNAPTIC CLEFT IS A COMPARTMENT THROUGH WHICH
NEUROTRANSMITTERS TRAVEL FROM THEIR RELEASE AT THE
PRESYNAPSE TO A RECEPTOR AT THE POSTSYNAPTIC MEMBRANE.
THE NTs MOVE BY DIFFUSION TAKING ABOUT ½ msec TO ARRIVE AT
THEIR RECEPTORS. AFTER BINDING TO THEIR RECEPTORS, NTs
MAY BE ENZYMATICALLY BROKEN DOWN (e.g. ACETYLCHOLINE BY
THE ACTION OF ACETYLCHOLINESTERASE) OR TAKEN BACK UP
AGAIN BY THE PRESYNAPSE (e.g. NOREPINEPHRINE IS TAKEN BACK
UP BY A TRANSPORT PROTEIN).
VESICLE
PRESYNAPSE
POSTSYNAPSE
FROG NEUROMUSCULAR SYNAPTIC CLEFT. CLEFTS ARE TYPICALLY
~200 ANGSTROMS WIDE.
POSTSYNAPTIC RECEPTOR PROTEINS
THE RECEPTORS THAT BIND WITH NEUROTRANSMITTERS MAY BE
DIVIDED INTO TWO MAIN FAMILIES AND SERVERAL SUB-FAMILIES:
VOLTAGE GATED CATION
(USE G PROTEINS)
TRANSMITTER GATED ION
(LIGAND GATED)
Na+ CHANNELS (e.g. ACETYLCHOLINEM )
K+ CHANNELS (e.g. THE SAME)
Ca+2 CHANNELS
ACETYLCHOLINEN CATION ex
GLUTAMATE GATED Ca+2 ex
SEROTONIN GATED CATION ex
gABA GATED Cl- in
GLYCINE GATED Cl- in
IN ADDITION, ACETYLCHOLINE RECEPTORS ARE ALSO DIVIDED INTO
TYPES THAT ALSO BIND TO EITHER NICOTINE OR MUSCARINE:
IF WE CONSIDER ACETYLCHOLINE, IT WILL BIND TO EITHER A NICOTINIC
OR A MUSCARINIC RECEPTOR. A NICOTINIC RECEPTOR HAS THE
APPEARANCE SHOWN HERE:
THIS RECEPTOR OPENS A PASSAGE (HOLE) FOR Na+ ENTRY. NICOTINE
ALSO BINDS TO THE RECEPTOR. THIS TYPE OF RECEPTOR IS FOUND
ON MUSCLE TISSUES (NEUROMUSCULAR JUNCTION).
TWO RATHER WELL-KNOWN SUBSTANCES: CURARE AND COBRATOXIN
ALSO BIND TO THE NICOTINIC ACETYLCHOLINE RECEPTOR TO CAUSE
PARALYSIS.
ORIGINALLY, CURARE
WAS PLACED ON ARROWS
AND DARTS FOR HUNTING.
IT KILLED ANIMALS BY
PARALYSIS OF LUNG
MUSCLES. THE WORD IS
DERIVED FROM THE SOUTH
AMERICAN INDIAN WORD:
WOORARI “POISON”.
MUSCARINIC ACETYLCHOLINE RECEPTORS MAKE USE OF G PROTEINS
TO ACHIEVE A POSTSYNAPTIC EFFECT WHICH MAY CAUSE DEPOLARIZATION OR HYPERPOLARIZATION (INHIBITION). HERE IS AN EXAMPLE
OF ONE RECEPTOR THAT CAUSES HYPERPOLARIZATION.
AFTER ACETYLCHOLINE
BINDS TO THE RECEPTOR
IT ACTIVATES A G PROTEIN
(TOP PICTURE). IN THIS
CASE THE G subg and subb
SUBUNITS (RATHER THAN
THE suba subunit) DIFFUSE
TO A POTASSIUM CHANNEL
PROTEIN AND CAUSE IT TO
OPEN.
THIS CAUSES K+ TO FLOW
OUT OF THE POSTSYNAPTIC CELL AND HYPERPOLARIZE (IT BECOMES
MORE NEGATIVE AS SHOWN
ON THE BOTTOM). THIS IS A MECHANISM USED IN HEART TISSUE TO
SLOW DOWN THE HEART RATE.
AN EXAMPLE OF TREATING PARKINSON’S DISEASE BY USING
NEUROTRANSMITTER REPLACEMENT – ALLEVIATING NEUROPATHOLOGY
PARKINSON’S DISEASE AFFECTS PATIENTS BY ADVERSLY AFFECTING
VOLUNTARY MOVEMENT (e.g. WALKING) AND PRODUCING INVOLUNTARY
TREMOR. THE DISEASE IS RELATED TO A DEGENERATION OF NEURONS
THAT PRODUCE DOPAMINE AS A NEUROTRANSMITTER (SEE THE
SYNTHETIC PATHWAY FOR NOREPINEPHRINE). THESE PATIENTS CAN BE
TREATED WITH AN AGONIST (REPLACEMENT THAT STIMULATES THE
DOPAMINE RECEPTOR) KNOWN AS BROMOCRIPTINE. THIS IS AN ARTIFICIAL
WAY OF SUPPLEMENTING THE LOSS OF DOPAMINE IN THE CNS THAT IS
NEEDED FOR NORMAL MOTOR (MUSCLE) FUNCTIONS.
WHAT IS IMPORTANT TO KNOW?
1) THE CONDUCTION PROPERTIES OF UNMYELINATED AND MYELINATED
NERVES.
2) HOW DOES A GATED SODIUM CHANNEL PROTEIN WORK?
3) WHAT ARE SODIUM CHANNEL TOXINS? (WHAT DO THEY DO?)
4) WHY WOULD OUR SPINAL CHORDS BE AS BIG AS TREE TRUNKS
WITHOUT MYELINATED NERVES?
5) WHAT HAPPENS IN THE PRESYNAPTIC AREA TO VESICLES WHEN
CALCIUM CHANNELS OPEN?
6) WHAT IS DOPA? WHAT DO NOREPINEPHRINE AND EPINEPHRINE
HAVE IN COMMON?
7) WHAT IS A “KISS AND RUN” MECHANISM FOR VESICLE OPENING?
8) WOULD YOU CONSIDER ENDORPHINS TO BE NEUROTRANSMITTERS
ACCORDING TO THE CRITERIA THAT QUALIFY SUBSTANCES TO BE NTs?
9) WHAT ARE THE TWO GENERAL KINDS OF ACETYLCHOLINE RECEPTORS
AND WHAT MECHANISM DO THEY USE TO ACHIEVE A POSTSYNAPTIC
EVENT (EFFECT)?
10) WHAT IS BROMOCRIPTINE AND WHY IS IT USED?