Synaptic Transmission & Receptor

Synaptic Transmission

단일 신경세포: 같은 종류의 neurotransmitter를 그 세포의 모든 synapse에서 씀
Co-existence of more than one transmitter substance
Four biochemical steps in synaptic transmission
1)합성 2)분비 3) postsynaptic receptor와 binding 4) 제거

Four criteria to be considered as transmitters
1) neuron에서 합성
2) presynaptic terminal에 있어야
postsynaptic neuron 또는 effector organ에 영향 줄 만큼 분비되어야
3) exogenous application (at resonable [])---> activity를 보여야
4) synaptic cleft에서 제거하는 특정기작이 있어야

Fig. 3.7 neurotransmitters

spinal cord의 motor neuron에---> neuromuscular jx.
autonomic nervous system
CNS: nucleus basalis에 많다---> cerebral cortex로

Amino acids
glutamate: most widespread excitatory transmitter in the CNS
aspartate: (glu & asp: Kreb's cycle의 product)
GABA: most widespread inhibitory transmitter in the CNS
glutamate--->GABA (glutamic acid decarboxylase)
glycine: inhibitory in the motorneuron

Monoamine neurotransmitters
Serotonin (5-hydroxutryptamine, 5HT): tryptophan에서 유래
brain stem의 midline raphe nuclei에 많다.
catecholamines: derived from tyrosine
:brain stem의 LC (신피질, 척추, 소뇌로 projection)
CNS와 PNS에서 mediating excitation or inhibition
Histamine: histidine에서 유래, hypothalamus에 많다.
invertebrate에 많다.
binding to specific receptors in the postsynaptic membrane
---> change membrane conductances
Na+ (with K+)---> excitation
K+ or Cl-----> inhibition
excitation or inhibition depends
only on the ion-channel properties of the receptor
and not on the transmitter substance itself.
e.g.: ACh: excitation at the neuromuscular junction
(nicotinic ACh receptor)
slows the heart (inhibitory muscarinic ACh receptor)

Peptidergic transmitters (synaptic modulators)

neurotransmitter의 4 조건을 모두 만족시키는
neuropeptide는 그리 많지않다.
do not directly change the conductance of the synaptic 막
influence the intensity and duration of the action of the
classical transmitters (sometime coreleased)
e.g.: enkephalin, substance P :(pain sensation)
beta-endorphib, adrenocorticotropin: stress 조절
angiotensin II, VIP, somatostatin, LHRH etc.

적어도 10 families of neuroactive peptides
각 family는 구조적으로 비슷
--> 비슷한 기능, 비슷한 receptors

Neurotransmitter의 합성:

대부분의 small-molecule transmitter는 presynaptic terminal에서 합성
peptide transmitter는 cell body에서 만들어지고 vesicle과 함께
terminal로 transpost된다.

Synthesis and storage of different types of neurotransmitters: (a) Peptide: (1) A precursor peptide is synthesized in the rough ER; (2) the precursor peptide is cleaved in the Golgi apparatus to yield the active neurotransmitter; (3) secretary vesicles containing the peptide bud off from the Golgi apparatus; (4) the secretary granules are transported down the axon to the terminal where the peptide is stored. (b) Amine and amino acid neurotransmitters: (1) Enzymes convert precursor molecules into neurotransmitter molecules in the cytosol; (2) transporter proteins load the neurotransmitter into synaptic vesicles in the terminal, where they are stored.

Slow autonomic synapse
Fig. 3.8
a synaptic potential at a peptidergic synapse in a sympathetic ganglion
EPSP lasts for minutes (spinal nerve stimulation후)
LHRH도 같은 효과: long-lasting depolarization
---> enhance the transmission of excitation at fast synapses
---> increasing effectiveness for a relatively long time


19세기 말: German biological chemist, Paul Ehrlich의 notion of Receptor
후에 Henry Dale, Eliot Smith에 의해 receptor theory 확립
Receptor: two common biochemical features:
1: membrane-spanning proteins
cell 밖의 부분에 의해 transmitter recognize & bind
2: carry out effector function within the target cell
ion channel을 직,간접적으로 gating--->
initiating a second-messenger cascade

Chemical Receptors Use two Major Molecular Mechanisms to Gate Ion Channels

Directly gating receptors (Fig. 9-10)
single macomolecule containing several subunits
(recognition site---> conformational change-->
open ion channel element)
ACh, glutamate, glycine, GABA등

Indirectly gating receptors
separate receptors (single polypeptide chanin)
and ion channels
(coupled by GTP binding proteins, G proteins)
secon messenger(cAMP, diacyglycerol) activation
(acts on channel directly) or
activation of protein kinases
phosphorylating either channel protein
or regulatory proteins
G protein also can directly act on the channels

Agonists and antagonists of synaptic transmission

transmitter binds to a receptor--> increase conductance for ions
receptor specificity is not absolute
receptor can bind to agonist (which relaces the transmitter)
similar action as the transmitter
e.g.: acetycholine agonists at the end plate
carbamylcholine, suberyldicholine
partial agonists
do not induce conductance change as effectively
cause no conductance change, prevent agonists from acting
competitive antagonist:
competes with the agonist for the binding site
e.g.: acetylchoine
curare: muscle paralysis
curare와 그 analogous substances--> muscle relaxant

Limiting the duration of transmitter action
transmitter diffuses in(and away from) the synaptic cleft.
at end plate: action duration about 1 ms.
destruction and removal of the transmitter.
Acetylcholinesterase: acetylcholine---> acetyl + choline.
Acteylcholinesterase released from presynaptic membranes and from
muscle fibers to the basement membrane at end plate.
during diffusion across the synaptic cleft 분해.
within few msec: all ACh broken down by the cholinesterase.
Fig. 3.9
curare action (South American Indian's arrow head)
Eserine (cholinesterase inhibitor)
---> end-plate potential's amplitude & duration increase
thrapeutic effect: curare-paralyzed muscle
counteract the muscle relaxation in 마취
Myasthenia gravis
insectide poison
chemical weapon---> prolonged activation of cholinergic synapses
especially in the ANS
Transport mechanisms:
synaptic cleft에서 rapidly removed or decomposed
presynaptic terminal에서도 transport-->
reduces the need for resynthesis of the transmitter

Myasthenia gravis
:skeletal muscle의 tone과 contraction이 약화
눈뜨기 힘들다, 거의 걷지 못한다.
원인: ACh receptor의 density가 적다. ACh release양은 정상

autoimmune disease--> develop antibodies to their own ACh receptors
cholinesterase inhibitors(ambenonium. neostigmine, pyridostigmine)
가 도움이 됨