Download Steps in chemical synaptic transmission and Ca2+ involvement Step

•
Steps in chemical synaptic transmission and Ca2+ involvement








Step 1: Neurotransmitter molecules are packaged into
membranous vesicles (synaptic vesicles), which are
concentrated and docked at the presynaptic terminal through
the help of kinesin
Step 2: The presynaptic membrane depolarizes, usually as
the result of an action potential
Step 3: The depolarization causes voltage-gated Ca2+
channels to open and allows Ca2+ ions to flow into the
terminal
Step 4: The resulting increase in Ca2+ triggers fusion of the
synaptic vesicles with the presynaptic membrane
Step 5: The transmitter is released into the extracellular
space in quantized amounts and diffuses passively across
the synaptic cleft.
Step 6: Some of the transmitter molecules bind to
receptors in the postsynaptic membrane, and the
activated receptors trigger a postsynaptic event, usually
the opening of an ion channel or the activation of a G
protein–coupled signal cascade.
Step 7: Transmitter molecules diffuse away from
postsynaptic receptors and are eventually cleared away
by continued diffusion, enzymatic degradation, or active
uptake into cells.
o Time from presynaptic AP to postsynaptic effect is
very short, ~200 μsec for small vesicles
•
Neuromuscular junctions and Ach
• We’re in the PNS, so axons are myelinated by Schwann cells
• Each motor axon terminal has clusters of vesicles filled with ACh
• AP causes vesicles to fuse with the terminal membrane
• Diffuses across synaptic cleft and through the basal lamina to reach postsynaptic
receptors at troughs in the muscle surface across from vesicle clusters
• Neurotransmitter removal: ACh is split into acetate & choline by
acetylcholinesterase in the synaptic cleft; choline then transported back to the
presynaptic ending for further synthesis of ACh
•
Ionotropic and Metabotropic receptors
• Ionotropic receptors: fast-acting, transmitter-gated ion channels
• Metabotropic receptors: slow synaptic transmission; binding of neurotransmitter
leads to altered concentrations of second messengers
•
Ach example
• Nicotinic (ionotropic receptor) found at neuromuscular junctions
• Can produce muscle contraction (fast EPSP)
• Muscarinic (metabotropic, G protein-coupled receptor) found on
smooth & cardiac muscle fibers, & on many neurons
• Can produce a decrease in heart rate through increased opening of
K+ channels and slow IPSP
•
Cholinergic, Noradrenergic, dopaminergic, serotonergic, histaminergic projection
systems (primary locations of cell bodies, functions, and drugs that act on these systems)
•
Neuropeptides (neuroactive peptides) usually stored and released from the same neurons
as one of the small neurotransmitters
• Metabolically expensive; present and effective at low concentrations
• Endorphins (endogenous substance with morphine-like actions)
• Substance P: originally described as a smooth muscle relaxant isolated
from gut, has been localized in synaptic endings in basal ganglia and DRG
• Enkephalins: prominent role in pain-control circuitry
•
Small neurotransmitters are each stored & released by separate sets of neurons
• Amino acids: glutamate, GABA, and glycine
• Monoamines: acetylcholine, serotonin, histamine
• Catecholamines: dopamine, norepinephrine, epinephrine
• Purine derivatives: ATP
Cholinergic: acetylcholine, ACh, mediates rapid, point-to-point transmission in PNS
• Mainly excitatory effect, sometimes inhibitory
• Cholinergic neurons of the CNS are concentrated in the brainstem, basal
forebrain, and basal ganglia
• Regulate general activity level of CNS neurons
•
•
Norepinephrine affects entire CNS
• NE activates mostly excitatory receptors, some inhibitory receptors
• Secreted by most postganglionic neurons of the sympathetic nervous
system
• Fight or flight; arousal, attention, stress/panic
• Main locations of neurons that (cell bodies)produce NE: Locus ceruleus, lateral
tegmental area, reticular formation of the brainstem
• Alertness, mood
•
Dopamine-containing neurons are scattered throughout the CNS
• Substantia nigra – midbrain; projects to the striatum (caudate & putamen)
facilitating voluntary movement
• Degeneration of dopaminergic cells in the substantia nigra produces
Parkinson’s disease
• Ventral tegmental area – midbrain; projects to part of the forebrain
(prefrontal cortex) and parts of the limbic system
• Implicated in neural systems that mediate reinforcement or reward as
well as aspects of drug addiction and psychiatric disorders (Schizophrenia)
•
Serotonergic raphe neurons associated with mood control
•
Histamine
• Raphe nucleus, reticular formation
• Sleep-wake cycle
•
Glutamate and GABA
• Glutamate: the major transmitter for fast, brief, excitatory synaptic events in
CNS
• One of the transmitters at ~90% of CNS synapses
• Acts on 4 major types of receptors, 1 metabotropic (G protein-coupled)
and 3 ionotropic (AMPA, NMDA, and Kainate)
• NMDA is responsible for some forms of long-term potentiation (LTP)
•
•
GABA (γ-aminobutyric acid) and glycine: the major transmitters for fast, brief,
inhibitory synaptic events in CNS
• Glycine localized to spinal cord; GABA everywhere
Any clinically relevant details
• Drugs
• Cocaine
• blocks reuptake of norepinephrine and dopamine
•
Amphetamine
• causes enhanced neurotransmitter release (norepinephrine and
dopamine)
•
Cannibus
• Hinders GABA inhibition  more dopamine activation
•
LSD
•
Affects seratonergic system
•
Ecstasy
• Acts simultaneously as a stimulant and a hallucinogen because
of its molecular structure, which is similar to that of both
amphetamines and LSD
• Blocks the reuptake pumps for certain neurotransmitters, thus
increasing their levels in the synaptic gap and their effect on the
post-synaptic neurons’ receptors
• Potentiates the effects of norepinephrine and dopamine, it is
distinguished from other psychostimulants by its strong affinity
for serotonin transporters
•
Benzodiazepines (i.e., diazepam - Valium) increase the frequency of
channel opening and can increase the Cl- conductance of the GABAA
receptor
•
Barbiturates (i.e., Phenobarbital) increase the duration of channel
opening
•
Depression Tx
• SSRIs used to treat depression (Prozac) block serotonin reuptake,
prolonging serotonin effect in the brain
• MAOIs prevent breakdown of serotonin
•
Excitotoxicity
• Prolonged exposure to glutamate (through excessive release or deficient
reuptake) can injure or kill neurons – excitotoxicity
• Initiated by excessive Ca2+ entry through NMDA receptors
•
In review
• Fast excitatory
• PNS: ACh (nicotinic receptors)
• CNS: glutamate
• Fast inhibitory
• GABA (GABAA, mostly in brain)
• Glycine (mostly in spinal cord)