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
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
