Cholinergic Pharmacology Flashcards
What are muscarinic cholinergic receptors (mAChR) and by which cells are they expressed?
mAChR are seven-transmembrane-domain G protein-coupled receptors (GPCRs) and expressed at the terminal synapses of all parasympathetic postganglionic fibers and a few sympathetic postganglionic fibers, at autonomic ganglia, and in the CNS.
What are nicotinic cholinergic receptors (nAChR) and by which cells are they expressed?
nAChR are ligand-gated ion channels that are concentrated postsynaptically at many excitatory autonomic synapses and presynaptically in the CNS.
What is the function of acetylcholinesterase (AChE)?
AChE is the enzyme responsible for acetylcholine degradation.
How is ACh synthesized?
ACh is synthesized in a single step from choline and acetyl coenzyme A (acetyl CoA) by the enzyme choline acetyltransferase.
Why is the incorporation of choline into phosphatidylcholine so essential?
Because choline itself cannot cross the blood-brain barrier.
What is the role of citrate in the production of acetylcholine?
It is hypothesized that citrate serves as the carrier for acetyl CoA from the mitochondrion to the cytoplasm, where citrate is freed by citrate lyase.
What is the rate-limiting step of ACh synthesis?
The rate-limiting step of ACh synthesis is mediated not by choline acetyltransferase, but rather by the availability of the choline substrate, which depends on uptake of choline into the neuron.
Which two processes are responsible for choline transport?
The first is low-affinity facilitated diffusion. This transport system is not saturable and is found in cells that synthesize choline-containing phospholipids, such as the corneal epithelium.
Far more important is a sodium-dependent, high-affinity transport system specifically found in cholinergic nerve terminals. Because the high-affinity transporter is easily saturated (at concentrations of choline > 10 μM), it sets an upper limit of the supply of choline for ACh synthesis. As the rate-limiting component, this transporter is a target for several anticholinergic drugs (e.g., hemicholinium-3).
After its synthesis in the cytoplasm, how is ACh transported into synaptic vesicles for storage?
Transport of protons out of the vesicle (i.e., down the H+ concentration gradient) is coupled to uptake of ACh into the vesicle (i.e., against the ACh concentration gradient) via an ACh-H+ antiport channel.
Which anticholinergic drug targets the ACh-H+ antiport channel?
Vesamicol. By inhibiting the ACh-H+ antiport channel, this drug lowers ACh storage and subsequent release.
In addition to ACh, cholinergic vesicles contain…
ATP and heparan sulfate proteoglycans, both of which serve as counter-ions for ACh. By neutralizing the positive charge of ACh, these molecules disperse the electrostatic forces that would otherwise prevent dense packing of ACh within the vesicle. Released ATP also acts as a neurotransmitter, through purinergic receptors, to inhibit the release of ACh and norepinephrine from autonomic nerve endings.
Which transporter is inhibited by hemicholinium?
The high-affinity Na+-choline co-transporter that allows for transport of choline into presynaptic cholinergic nerve terminals.
What is the molecular basis for Lambert-Eaton myasthenic syndrome (LEMS)?
LEMS results from an autoantibody that blocks the presynaptic Ca2+ channel.
What is the function of botulinum toxin?
Botulinum toxin prevents the exocytosis of presynaptic vesicles, thereby blocking ACh release.
Which cholinergic receptors are excitatory and which are inhibitory?
Postsynaptic nicotinic receptors and M1, M3, and M5 muscarinic receptors are excitatory; postsynaptic M2 and M4 muscarinic receptors are inhibitory.
Presynaptic nicotinic receptors enhance Ca2+ entry into the presynaptic neuron, thereby increasing vesicle fusion and release of ACh; presynaptic M2 and M4 muscarinic receptors inhibit Ca2+ entry into the presynaptic neuron, thereby decreasing vesicle fusion and release of ACh.
Most clinically relevant anticholinesterases are competitive inhibitors of the enzyme. True or false?
True.
At which sites in the body does muscarinic cholinergic transmission mainly occur?
Muscarinic cholinergic transmission occurs mainly at autonomic ganglia, at end organs innervated by the parasympathetic division of the autonomic nervous system, and in the CNS.
Human muscarinic receptors form two functionally distinct groups. What differentiates these two groups?
M1, M3, and M5 are coupled to G proteins responsible for the stimulation of phospholipase C; M2 and M4, on the other hand, are coupled to G proteins responsible for adenylyl cyclase inhibition and K+ channel activation.
In which tissues are M1 receptors expressed?
M1 receptors are expressed in cortical neurons and autonomic ganglia.
In which tissue are M2 receptors expressed?
M2 receptors are expressed in cardiac muscle.
In which tissues are M3 receptors expressed?
M3 receptors are expressed in smooth muscle and glandular tissue.
Open channels of the activated nAChR are equally permeable to K+ and Na+ ions. True or false?
True. However, since the resting membrane potential is close to the Nernst potential for K+ and far below the Nernst potential for Na+, the predominant ion passing through the open nAChR is Na+.
Why is the depolarization mediated by nAChRs brief (
Because ACh dissociates rapidly from active-state receptor molecules and acetylcholinesterase rapidly degrades free (unbound) ACh in the synaptic cleft.
How many subunits make up a nAChR?
Five subunits. Each receptor at the neuromuscular junction (NMJ) is comprised of two ⍺ subunits, one β and one δ subunit, and either one γ subunit or one ɛ subunit.
What is the difference between nicotinic cholinergic receptors at autonomic ganglia and in the CNS (termed N2) and those at the NMJ (termed N1)?
The subunits in N2 receptors are composed solely of ⍺ and β subunits.
How many different ⍺ and β subunit types have been detected in neuronal tissues?
Nine different ⍺ subunit types (⍺2 - ⍺10) and three β subunit types (β2 - β4). (⍺1 and β1 refer to the distinct subunit types found at the NMJ.)
Where is AChE concentrated?
AChE is concentrated on the postsynaptic membrane.
What is butyrylcholinesterase (BuChE) and what roles does it play in ACh degradation?
BuChE is also known as pseudocholinesterase or nonspecific cholinesterase. BuChE plays a secondary role in ACh degradation. Recent evidence suggests that BuChE may play a minor role in early neural development as a co-regulator of ACh (it can hydrolyze ACh, but at rates much slower than AChE) and may be involved in the pathogenesis of Alzheimer’s disease.
