Chapter 7: Acetylcholine Flashcards
Acetylcholine
found in neuromuscular junctions and synapses in autonomic nervous system
- sympathetic (preganglionic)
- parasympathetic (preganglionic and postganglionic)
Location in CNS
Striatum (in basal ganglia)
Interneurons
Basal Forebrain Cholinergic System (BFCS):
- basal nucleus
- diagonal band nucleus
- substantia innominata
Tegmental Pons (goes everywhere except forebrain):
- LDTg
- PPTgAcetylcholine Target
Hippocampus, amygdala, and cortex
ACh Receptors
Ionotropic: nicotinic cholinergic receptors (blocked by curare)
5 Subunits:
- In PNS: alphax2, beta, gamma, delta
- in CNA: alphax2, betax3
Metabotropic: muscarinic cholinergic receptors (blocked by atropine)
ACh is synthesized in […]
ACh is synthesized in a single enzymatic step
Precursors: choline (mainly from fat in diet and form liver) and acetyl CoA (generated in all cells by metabolism of sugars and fats)
Enzyme: choline acetyltransferase (ChAT)
- in cytoplasm, found only in neurons that use ACh as NT
- transfers -COCH3 from acetyl CoA to choline
Synthesized to ACh and Coenzyme A
Rate of ACh synthesis is controlled by
- availability of precursors
- rate of cell firing
[…] into the […] is the rate- limiting step of ACh synthesis
Choline uptake into the nerve terminal is the rate- limiting step of ACh synthesis
Choline transporter in the the nerve terminal
- blocked by hemicholinium-3 (HC-3), reducing ACh synthesis
Choline transporter KO mice
- die within an hour of birth - lack of ACh at NMJ impairs breathing
ACh is loaded in vesicles by […]
ACh is loaded in vesicles by VAChT
vesicular ACh transporters (VAChT)
- located in vesicle membrane
vesamicol- doesn’t affect rate of ACh synthesis
- blocks VAChT
- reduces amount of ACh released when neurons fires
- increases ACh levels in cytoplasm
- Cholinergic vesicles still present and undergoing exocytosis, but amount of ACh in vesicles is low
ACh is affected by various toxins
Black widow spider venom
- massive release of ACh in the PNS
- muscle pain, tremors, nausea, vomiting, salivation, copious sweating
Botulinum toxin
- clostridium botulinum
- inhibits ACh release
- BoTox- local paralysis to reduces wrinkles
ACh is degraded by […]
ACh is degraded by AChE
breaks acetylcholine back into choline and acetic acid
- choline taken back up into cholinergic nerve terminals by choline transporter
Located in:
- presynaptic neuron- metabolizes excess ACH that has been synthesized - postsynaptic membrane- breakdown ACh after released into synaptic cleft - basal lamina of NMJ- enzyme molecules become immobilized by attaching to other proteins in NMJ
AChE is the target of some beneficial substances and some deadly substances
- drugs that lock AChE prevent inactivation of ACh so postsynaptic effects of ACh
Alzheimer’s drugs: significant loss of forebrain cholinergic neurons
- reversible AChE inhibitors: drug molecules bind temporarily to enzyme protein to inhibit actions, but after drug dissociates from enzyme ACh breakdown is restored
- all synthetic compounds that enter brain
- donepezil (Aricept)
- rivastigmine (Exclon)
- galantamine (Reminyl)
Clinically useful substances:
- Physostigmine (crosses the BBB), used to treat glaucoma - Neostigmine (Prostigmin) and pyridostigmine (Mestinon) (do NOT cross the BBB), used to treat myasthenia gravis
Myasthenia gravis
antibodies formed against skeletal muscle cholinergic receptors
- block receptors and then break then down by muscle cells - severe weakness and fatigue
Organophosphates
- irreversible AChE inhibitors
- can occur either because dissociation of compound from enzyme is really slow or compound forms covalent chemical bond with enzyme - insecticides
- nerve agents (soman, sarin, VX)- designed to be dispersed as vapor cloud or spray, which allows entry into body through skin contact inhalation
Exposure results in:
- profuse sweating, salivation, vomiting, loss of bladder and bowel, convulsions and death by asphyxiation
Tegmentum
LDTg- goes to ventral tegmental area
PPTg- goes to substantia nigra
Have excitatory projections to brain stem and thalamic area that play important roles in behavioral arousal, sensory processing, and initiation of REM
Ionotropic Acetylcholine Receptors
- Each subunit has 4 transmembrane domains
- TMD 2 (M2) lines the pore
- have necessary amino acid needed to pass the ions through which strips the water (water of hydration) - channels open rapidly and Na+ and Ca2+ flow in ( and some K+)
Agonists: nicotine and succinylcholine (powerful muscle relaxant that induces brief paralysis)
Antagonists: curare and mecamylamine (blocks receptors in central and autonomic ganglia)
Ionotropic Receptor Subunits
NMJ: alpha x2, beta, gamma, delta
Typical brain receptor: alpha4beta2 (alpha x2, beta x3)
Homomeric - 5 identical subunits
- alpha7 - permeable to Ca2+ (second messengers important in neuroplasticity)
Transition states of ionotropic receptor
- Closed- NT not bound and channel pore is closed
- non-conducting - Open- binds to agonist and pore opens and ions can flow across membrane
- conducting - Desensitized- closed but can’t be opened
- agonist can still be bound
- other portion of pore is closed
- non-conducting
Metabotropic Receptors
- 7 transmembrane domain, GPCR
- 5 subtypes
- M1- M5
- LDTg input to VTA activates M5, modulates DA firing, behavioral relevance of stimuli
- Parasympathetic control of cardiac muscle involves M2
- slowed heart rate and decreased strength of contraction
Found in neocortex (cognition), hippocampus, thalamus, striatum (motor function) and basal forebrain
- Cardiac muscle of heart, smooth muscle of organs, in secretory gland
- activated by ACh released from postganglionic fibers of PNS
Agonists: muscadine and pilocarpine
Antagonists: atropine and scopolamine
*stimulates K+ channel opening
AChE modulates firing of […] neurons in […]
AChE modulates firing of DA neurons in VTA, cortical and behavioral arousal
ACh has diverse roles
PNS: NMJ (nAChR), Autonomic ganglia (nAChR and mAChR), parasympathetic NS (mAChR)
CNS: cognition
ACh has diverse roles in cognition
memory consolidation, sensory attention, behavioral arousal
Deficits in ACh signaling are involved in dementia
mACh receptor antagonists are […]
mACh receptor antagonists are amnestic
Scopolamine or atropine impair performance on learning tasks
- classical conditioning, discrimination learning, spatial learning - active and passive avoidance tasks delay tasks
mACh receptor antagonists have been used to model memory deficits in AD
- exacerbate cognitive impairments of patients with AD
Memory impairments may result from deficits in […]
Memory impairments may result from deficits in sensory attention
ACh is released in PFC
- from the BFCS
- phasic (or transient) release
- associated with detection of cues (“hits”) in attention tasks
ACh stimulate […] release from the […]
Arousal
Increases DA release
Increases behavioral activation
The attentional hypothesis
- Arousal
- cortical potentiation
- subcortical- sleep; behavioral activation - Attention to stimuli guiding behavioral responses
- Memory
