Topic 5: Acetylcholine Receptors Flashcards
Where does cholinergic neurotransmission occur?
neuromuscular junctions: where motor neurons connect to muscle
CNS
autonomic nervous system (ANS): preganglionic neurons of the sympathetic and parasympathetic branch, ganglionic neurons of the parasympathetic branch
What are agonists of muscarinic receptors?
agonists of muscarinic receptors are parasympathomimetic, as they mimic effects of activation of the parasympathetic nervous system
mimics parasympathetic nervous system
What are antagonists of muscarinic receptors?
antagonists of muscarinic receptors are parasympatholytic, as they inhibit parasympathetic functions
What is the striatum?
involved in motor function
ACh balances out dopamine; if out of balance, Parkinson’s
ACh involved in motor function
What is the dorsolateral pons?
involved in arousal (reticular activating system) and addictions
What is the BFCS?
basal forebrain cholinergic system; learning, memory, and attention
cholinergic neurons located in medial septum, diagonal band nuclei, nucleus basalis, and substantia innominate
projections to cortex, hippocampus, amygdala
loss of BFCS cholinergic neurons is associated with cognitive decline in Alzheimer’s disease
implicated in memory and attention
What is atropine?
plant alkyloid found in the nightshade plant
antagonist of the muscarinic ACh receptor: blocker of receptor, inhibit parasympathetic function
administered opthalamologically to dilate pupils: parasympatholytic effect (inhibiting parasympathetic system)
BBB permeable
oral administration inhibits cognition in animals (acquisition and maintenance of learning tasks)
How does ACh in the BFCS impact cognition?
administration of atropine or the related scopolamine is amnesiac in humans
scopolamine and morphine was a drug combination often administered during labour in the early-mid 20th CE
scopolamine induces a “twilight sleep” avoiding both the pain and memory of labor (discontinued due to adverse effects on newborns)
ACh thought to be important for memory consolidation (esp. episodic) due to innervation of the hippocampus
alternately proposed to affect memory through effects on attention and sensory discrimination; we don’t remember because we aren’t paying attention to things
What was the microdialysis on ACh levels during attention?
using microdialysis researchers showed that ACh levels increased during tasks requiring sustained attention more so than comparative tasks
operant control task - reward task e.g. lever press for food reward
F19-s schedule of reinforcement - operant reward task with a predictable delay
only see drastic increase in ACh in attention task
What is saporin?
protein toxin isolated from soapwort plant (Saponaria officinalis)
water soluble toxin
highly specific inhibitor of ribosome function (ribosome inactivating protein - RIP)
can be conjugated to antibodies to target specific cell types (investigated as anti-cancer agent)
What is 192-IGG saporin?
conjugated to an antibody that targets basal forebrain cholinergic neurons
administration to ventricular system results in targeting of BFCS neurons and selective lesion of only the cholinergic cells
BFCS lesion produces specific deficits in learning, memory (esp. spatial), and attention
in sustained attention tasks animals lesioned with 192 IgG-saporin had a lower number of correct hits when the signal strength was weak suggesting deficits in attention
performance was comparable on other aspects of the task, suggesting no global cognitive or motor impairment
How does ACh interact with arousal systems?
ACh is one component of the reticular activating system
cholinergic projections from the pons (pedunculopontine nucleus and laterodorsal tegmental nucleus) are active while awake and trigger the transition to REM sleep
reticular activation also involved in increasing attention
How is ACh involved in addiction?
cholinergic neurons originating in the dorsolateral pons innervate the ventral tegmental area
ACh stimulates dopaminergic neurons projecting to the nucleus accumbens (reward circuitry)
nicotine activates nicotinic ACh receptors to directly activate dopaminergic neurons in the VTA
nicotine is an agonist to ACh acts on receptors within VTA
What are the two families of cholinergic receptors that are found in mammals?
nicotinic receptors (NAChR): 17 varieties, ionotropic receptors pass Na+ and Ca2+
muscarinic receptors (MAChR): 5 varieties, metabotropic receptors (G-protein coupled receptors)
What are nicotinic acetylcholine receptors?
NAChR are a family of ligand gated ion channels
permeable to Na+ and Ca2+
nicotine is a selective agonist of NAChR
found in neuromuscular junction, sympathetic, parasympathetic, and central nervous system
most popular agonist for this receptor is nicotine
How does a depolarization block work at nicotinic acetylcholine receptors?
NAChR desensitize (inactivate in the presence of a prolonges stimulus)
agonists that do not readily desensitize receptors cause a depolarization block (preventing the target cell from firing by preventing repolarization)
succinylcholine is a muscle relaxant that causes prolonged activation of NAChR and subsequent muscle paralysis; prevents you from dying put if you take to much they die
What are the functions of nicotinic receptor functions?
at the neuromuscular junction NAChR are always located post-synaptically (classic transmission)
in the CNS MAChR can be located in both post- or pre-synaptic membranes: pre-synaptic NAChR function to modulate neurotransmitter release - multiple types of neurons
NAChR antagonists include curare poison (D-tubocuraine); numerous tropical plants indigenous to S. America, used as an arrow poison for hunting (causes respiratory paralysis)
How does acetylcholine work in invertebrates?
ACh is a major neurotransmitter in insects
neuronal NAChR have wide expression but different composition and sensitivity than in mammals
neonicotinoid insecticides are broad spectrum insecticides that have low adverse effects in mammals (selectivity and BBB impermeable)
irreversible NAChR antagonists
What are muscarinic acetylcholine receptors?
5 types (M1 through M5 receptors)
all are metabotropic receptors (G-protein coupled receptors)
specific agonist muscarine isolated from the fly agaric mushroom
What is muscarine?
parasympathomimetic
ingestion leads to exaggerated parasympathetic response
lacrimation, sweating, salivation, pinpoint pupils, severe abdominal pain (strong concentration of smooth muscles and painful diarrhea)
high doses - cardiovascular collapse, convulsions, coma, death
What are G-protein coupled receptors?
7-transmembrane helix receptor family
coupled to specific GTP binding protein on the intracellular side
elicits effects on target cells through second messengers: cAMP, IP3, Ca2+
What are the three types of G-proteins?
Gs –> stimulates downstream targets
Gi –> inhibits downstream targets
Gq –> modulatory functions downstream
What is the Gq alpha/ PLC signaling cascade?
PLC activation cleaves PIP2 (membrane phospholipid) to IP3 (soluble) and DAG (lipid)
IP3 activates Ca2+ channels on the ER to trigger Ca2+ release into the cytoplasm
DAG activates protein kinase C in conjunction with Ca2+
PKC phorphorylates numerous cellular proteins
What is the G-protein coupling of M1, M3, and M5 receptors?
M1, 3, 5 –> Gq alpha –> phospholipase C –> IP3 and Ca2+ release
M1 involved in neurotransmission in autonomic ganglion cells (both sympathetic and parasympathetic) and cognitive effects in CNS
M5 involved in addictive behavior
