Synaptic transmission (today's lecture features channels)
channels (ionotropic) ACh, glutamate, GABA, Glycine
vs. metabotropic receptors- peptides and others

Review of major points (that mostly everybody knows), thus, since a lot is text book material, I only present a few references, the rest is from Alberts et al.

Chemical synaptic transmitter substances:
Monamines (acetylcholine, catecholamines, serotonin)
Peptides
Amino Acids
Nucleotides
Gasses

Presynaptic membrane, cleft, Postsynaptic membrane
Biochemistry - synaptosomes
Postsynaptic receptors, multiplicity defined by pharmachology
agonist, antagonist
Breakdown, reuptake

TRANSPARENCY Fig. 11-30, p. 537 Alberts et al. (SEM of neuromuscular junction)
on n.m.j. (100 - 1000 square microns as opposed to synapse - 1 square micron)
TRANSPARENCY Fig. 11-35, p. 541 Alberts et al. motor neuron - final common path
TRANSPARENCY Fig. 13-43, p. 632 Alberts et al., synaptic vesicle formation
TRANSPARENCY Fig. 11-34, p. 540 Alberts et al., ion channels of neuromuscular junction
(Here is where that information I mentioned in the "channels" outline about calcium channels comes in, so, for convenience, I repeat it here:)
In presynaptic terminal:Ca2+ in through Q or N type voltage gated channel
(N stands for "neither, as opposed to T=transient or L=long lasting, the N channel is blocked by omega toxin from Conus [snail genus])

In Muscle: t-tubules get excitation to near sarcoplasmic reticulum
dyhydropyridine (blocking drug) receptor in t-tubule
homology to sodium channel - voltage sensitive

In Muscle: ryanodine receptor in sarcoplasmic reticulum same family as IP3 receptor
coupled with t-tubule

D. W. Tingley, Evolutions: Synaptic transmission, Journal of NIH Research 7, Nov. 1995, 103-104 & 98-101. TRANSPARENCY

From Tingley, 1995 and other sources:
reticular theory - cells are not separated from each other
vs. Schwann's 1839 cell theory
1891 Waldeyer coined "neuron"
1897 Held described "boutons"
Muller had students - DuBois-Reymond (chemical communication)
and Helmholtz - electrical
early 1900's - 1932 Nobel for "functions of neurons" - Sherrington (England) Integrative Action of the Nervous System 1906 coined "synapse," studied spinal reflex
1904 - Elliot adrenalin from adrenal mimics sympathetic nerves
1905 - Langley - chemical transmission in fish
1921 Loewi vagus
1936 Dale - acetylcholine
share 1936 Nobel "chemical transmission of nerve impulses"
1953 Palay sees synapse in EM
1959 Furshpan and Potter electrical transmission in crayfish
1963 Nobel Prize - Eccles (with Hodgkin and Huxley) - Resistance decreases - channels open EPSP (PK & PNa up) IPSP(Cl- conductance)
1964 DeRobertis - omega figures
1965 Katz and Miledi - low calcium -> "quanta"
1970 Nobel Sir Bernard Katz (England) Ulf von Euler (Sweden),Julius Axelrod (US) "humoral transmitters...nerve terminals....storage release inactivation"
Science publishes Nobel speeches - Julius Axelrod, Noradrenalin: Fate and control of its biosynthesis, Science 173, 598-606, 1971
1974 Heuser et al quick freezing
early 1970's - Katz et al, use noise analysis to understand AChR
1976 Neher and Sackmann - record from individual channels
alpha-bungarotoxin binds nicotinic
1978 Karlin alpha, beta, gamma and delta
1980's cloning from Torpedo
Calcium channels (T, N, and L) - calcium entry critical
glutamate and GABA
work with NMDA and non-NMDA receptors
metabotropic receptors
proteins involved in vesicle
nitric oxide, etc

Aceylcholine "metabolism"

TRANSPARENCY
Dietary choline -reuptake or uptake-> intraneural choline
-Choline-O-acetyltransferase-> H3-CO-O-CH2-N+-(CH3)3
Acetyl Co-A
release stimulated by Ca2+, blocked by botulism
over release by black widow spider venom
nicotinic receptors - nicotine stimulates, curare blocks.
labeled by 125I alpha-bungarotoxin - banded krait - snake
receptors low in mysthenia gravis - autoimmunity to nicotinic receptors
autonomic ganglia, muscle
muscarinic receptors - muscarine stimulates, atropine (belladonna) blocks
parasympathetic neuro-effector junctions (incl. smooth muscle)
Acetylcholinesterase blocked by malathion and neostigmine

TRANSPARENCY from Axelrod's 1971 Nobel Prize speech
" Metabolism" of epinephrine (amine from amino acid)
(phenylalanine->) l-tyrosine -> (tyrosine hydroxylase, rate limiting)
-> l-DOPA (dihydroxyphenylalanine)
given to Parkinson's patients, precursor of quinones which polymerize to melanin
-> (DOPA decarboxylase = l-aromatic amino acid decarboxylase, low substrate specificity used also in 5HT=5-hydroxy tryptamine =serotonin synthesis)
-> dopamine (not l or d)
low in nigro-striatal dopamine system (from substantia nigra to striatum) in Parkinsons
-> (dopamine beta hydroxylase)
-> l-NE -> (PNMT [N-methyl transferase]) E
MAO breaks down intracellularly and inhibitors are antidepressants
COMT breaks down extracellularly
but by far, reuptake is the way that NE is inactivated

The Nicotinic Acetylcholine receptor (information from here and there)

TRANSPARENCY Fig. 11-32, p. 538 Alberts et al.
Torpedo - electric ray
up to 75 V (not that much) but 20 Amps
there are fish with electric sense, not just thost that stun prey
lots of generator potentials added up (Electrophorus - lots of spikes 600 V 1 A)
Structure likely spans the membrane 4 times (though there is extra alpha-helix)
expression - need all 4 types of subunit
autoimmunity in myasthenia gravis
mechanisms of muscular relaxatants used in surgery (like succinylcholine)
when nerve-muscle junction is made, diffuse receptors cluster
in Torpedo 10,000/micro meter2, i.e. 1 per 100 x 100 A
concentrated at n.m.j. crest, 20,000 - 30,000
whereas AChE is evenly distributed
6.5 A in diameter, probably water filled pore
0.2 - 3.0 x 106 ACh molecules from one a.p. into n.m.j. cleft
2.5 x 105 channels transiently open
400 nA n.m.j. end plate current
1 ms open time
10,000 Na+'s flow through each channel in this time
channel conductances of 25 pS

TRANSPARENCY - Fig. 11-31, p. 538 channel opening and closing
occupied and closed - analogy to inactivated vs closed

TRANSPARENCY - REVIEW channel structure Fig. 11-33, p. 539 Alberts et al

Amino acid transmitter systems

Glutamate central excitatory - like inputs to hippocampus
a lot of diversity
AMPA a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
reversal potential is at 0 mV so it is likely opening for K+ & Na+ channels
NMDA (N-methyl-D-aspartate) blocked by APV (2-amino-5-phosphonovalerate)
reversal is more positive, => open Na+ & Ca2+
Calcium influx - cytotoxicity in injury or stroke
(There are other cation selective subclasses defined pharmacologically)

GABA (gamma amino butyric acid)
GAD glutamic acid decarboxylase
GABAA is Cl- channel blocked by bicuculline & picrotoxin
Benzodiazepines (like Valium) bind- reduce anxiety
Barbiturates also enhance Cl- conductance

Glycine blocked by strichnine
5 subunits - 2 alphas & 3 betas
4 (?) membrane passes with M2 lining pore

A very simple experiment, (Miller 1998) (Rosenmund, Stern-Bach and Stevens 1998) the glutamate channel is suggested to be a tetramer.

Vesicle fusion

TRANSPARENCY Fig. 13-58, p. 645, Alberts et al. - proteins in vesicle fusion
TRANSPARENCY Fig. from D. W. Tingley, Synaptic-vesicle release: New pieces of a puzzling process (in focus) Dec. 1995 J. NIH Res. 7, 46-49
Here (Fig. 5.10) is the information in Purves et al., the text book I am currently using to teach my neuro course
Docking, Priming (requires ATP), Fusion/exocytosis, Endocytosis
Ca2+ in through Q or N type voltage gated channel
(N stands for "neither, as opposed to T=transient or L=long lasting, the N channel is blocked by omega toxin from Conus [snail genus] toxin
Membrane proteins and cytoplasmic proteins
also the names change to protect the innocent
Vesicle proteins:
Synaptobrevin / VAMP (vesicle-associated membrane protein) = v-SNARE
Botulinum and Tetanus toxin binding sites
synaptotagmin - binds calcium
Rab3 (like ras, small GTP binding protein) (lots of rab's, specific for transport)
synapsins get phosphorylated (by CaM Kinase and PKA) interact with actin
target membrane proteins:
Syntaxin = t-SNARE
Neurexin - black widow spider venom (alpha Latrotoxin)
Cytoplasmic:
NSF - N-ethylmaleimide sensitive factor (ATPase activity when complex dispersed)
SNAP - soluable NSF associated protein
rabphillin

Metabotropic receptors -> signalling
like for beta adrenergic receptor, CAPM increased, action potentiated by caffeine which is a cAMP phophodiesterase inhibitor

George Wald Nobel Prize 1967 rhodopsin
later they found that it was 7-TD receptor
Sutherland Nobel prize 1971 Signal transduction cAMP father of signal transduction

References


J. Axelrod, Noradrenalin: Fate and control of its biosynthesis, Science 173, 598-606, 1971

Rosenmund, C., Y. Stern-Bach, and C. F. Stevens, 1998 The tetrameric structure of a glutamate receptor channel [see comments]. Science. 280: 1596-9.

D. W. Tingley, Evolutions: Synaptic transmission, Journal of NIH Research 7, Nov. 1995, 103-104 & 98-101.

D. W. Tingley, Synaptic-vesicle release: New pieces of a puzzling process (in focus) Dec. 1995 J. NIH Res. 7, 46-49

This page was last updated on Dec. 19, 2001

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