Cholinergic Transmission Flashcards
what is cholinergic pharmacology centered around? what does is generally involve?
- centered around acetylcholine
- functions of the cholinergic pathways generally involve the neuromuscular junctions (NMJ), the autonomic nervous system and the central nervous system
how is Ach synthesized? how is it degraded?
- synthesized in single step from choline and acetyl coenzyme A (acetyl CoA) by choline acetyltransferase (ChAT)
- Acetylcholinesterase (AChE) is responsible for degredation fo Ach, it is also an important pharmacologic target
what are the two classes of cholinergic receptors
Muscarinic receptors
- G-protein linked and expressed at the terminal synpases of all parasympathetic post-ganglionic fibers and a few sympathetic postganglionic fibers at autonomic ganglia and in CNS
- alter cell signalling by activating second messanger systems
- 5 distinct genes that encode 5 human muscarinic receptors (M1 - M5)
Nicotinic receptors
- ligand gated ion channels
- concentrated postsynpatically at many excitatory autonomic synpases and presynpatically in the CNS
- futher classified based on their location at autonomic ganglia and in the CNS (NN) or at neuromuscular junction (NM)
how is Ach synthesized, what prevents this synthesis
- choline is transported into presynaptic cholinergic nerve terminal by high-affinit Na+- choline co transporter
*transporter is inhibited by hemicholinium
- is not inhibited, the cytosolic enzyme choline acetyltransferase catalyzes the formation of Ach from acetyl coenzyme A (AcCoA) and choline
once Ach is synthesized it is packaged with ____. Transport into vesicle is mediated be ____ and inhibited by _____
- newly synthesized Ach is packaged with ATP and proteioglycans into vesicles for storage
- transport of Ach into the vesicle id mediated by H+-ACh antiporter
- antiporter is inhibited by vesamicol
once Ach is in vesicles how is it released
- vesicles fuse with the plasma membrane when intracellular calcium levels rise in response to a presynpatic action potential
- this releases the neurotransmitter into the synpatic cleft
- Ach diffuses in the celf and binds to postsynpatic and presynpatic receptors
muscarinic receptors alter cell signalling pathways, how
activate phospholipase C, inhibit adenylyl cyclase (AC) and opening of K+ channels
what are teh excitatory receptors
- postsynaptic nicotinic receptors and M1, M3 and M5 muscarinic receptors
what are the inhibitory receptors
M2 and M4 muscarinic receptors
what do presynpatic nicotinic receptors do?
- enhance Ca2+ entry into the presynaptic neuron to increase vesicle fusion and release of ACh
What do presynpatic M2 and M4 muscarinic receptors do?
- inhibit Ca2+ entry into the presynpatic neuron
- decreases vesicle fusion and release of ACh
what decreades Ach, what inhibits the degredation
- degraded by membrane-bound acetylcholinesterase (AChE) into choline and acetate
- numerous inhibitors exist - most clincally relevant is anticholinesterases (competitive inhibitors)
Describe the location and action of the 5 muscarinic receptors
M1
- Location: some autonomic ganglia
- Action: increased activation
M2
- Location: Heart
- Action: decreased rate/force of contraction
M3
- Location: Smooth muscle, glands and endothelial cells
- Action: increased contraction, secretion and vasodilation
M4
- Location: CNS
- Action: Inhibitory
M5
- Location: CNS
- Action: Excitatory
what secondary messenger systems fo muscarinic receptors usually activate
increase inositol triphosphate (IP3) and diacylglycerol (DAG) and decrease cAMP (see below).
M1, M3 and M5 receptors
- Inc IP3/ DAG = excitatroy
- agonist activates receptor -> activates G-protein -> activates phospholipase C
- then PIP2 —> DAGto activate PKC
- OR PIP2 —> IP3 turned stored calcium itno free calcium to activate calcium dependent protein kinases
describe action of M2 and M4 receptors
- agonist activates receptor –> activates G-protein –> inhibits adenylyl cyclase
- decreases production of cAMP so it cant phosphorylate enzymes
describe cholinergic effects in blood vessels
- no parasympathetic input to blood vessels but cholinergic receptors are present on endothelial cells that line blood vessles
- result = direct agonists relax vascular smooth muscle
*agonist binds to muscarinic receptor whcih inc endothelial dervies relaxing factor (EDFR, nitric oxide) causing smooth muscle to relax
What are the types of nicotinic receptors, their location and action?
NN
- Location: Post-gnaglionic enurons, adrenal gland, CNS
- Action: Opens Na+ and K+ channels
NM
- Location: Skeletal muscle
- Action: Opens Na+ and K+ channels
describe the structural biology of the nicotinic acetylcholine receptor
- 5 subunits α2βεδ
- each subunit is composed of a transmembrane protein that has 4 membrane spanning (hydrophobic) alpha-helical regions (M1, M2, M3 and M4)
- the large hydrophilic N-terminal domains of the two alpha subunits contain the bidning sites for acetyl choline
