Transcript PSNS 2nd Lecture 1433 - Home - KSU Faculty Member websites

Pharmacology-1 PHL 313
Parasympathetic Nervous System
Second Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Cholinergic
Transmission
 The terminals of cholinergic neurons
contain large numbers of small
membrane-bound vesicles (containing
ACh) concentrated near the synaptic
portion of the cell membrane
 ACh is synthesized in the cytoplasm from
acetyl-CoA and choline through the
catalytic action of the enzyme choline
acetyltransferase (ChAT)
 Acetyl-CoA is synthesized in mitochondria,
which are present in large numbers in the
nerve ending
 Choline is transported from the
extracellular fluid into the neuron
terminal by a sodium-dependent
membrane carrier (carrier A). This
carrier can be blocked by a group of
drugs called hemicholiniums
The action of the choline transporter
is the rate-limiting step in ACh
synthesis
Cholinergic
Transmission
 Once synthesized, ACh is transported from
the cytoplasm into the vesicles by an
antiporter that removes protons (carrier B).
This transporter can be blocked by
vesamicol (cholinergic physiological antagonist)
 Release of ACh is dependent on
extracellular Ca2+ and occurs when an
action potential reaches the terminal and
triggers sufficient influx of Ca2+ ions
 The increased Ca2+ concentration
"destabilizes" the storage vesicles by
interacting with special proteins associated
with the vesicular membrane (VAMPs)
 Fusion of the vesicular membranes with the
terminal membrane results in exocytotic
expulsion of ACh into the synaptic cleft
 The ACh vesicle release process is blocked
by botulinum toxin (neurotoxic protein) through
the enzymatic removal of two amino acids
from one or more of the fusion proteins
Cholinergic
Transmission
 After release from the presynaptic terminal,
ACh molecules may bind to and activate an
ACh receptor (cholinoceptor)
 Eventually (and usually very rapidly), all of
the ACh released will diffuse within range of
an acetylcholinesterase (AChE) molecule
 AChE very efficiently splits ACh into choline
and acetate, neither of which has significant
transmitter effect, and thereby terminates
the action of the transmitter
 Most cholinergic synapses are richly
supplied with AChE; the half-life of ACh in
the synapse is therefore very short. AChE is
also found in other tissues, e.g., red blood
cells
 Another cholinesterase with a lower
specificity for ACh, butyrylcholinesterase
[pseudocholinesterase], is found in blood
plasma, liver, glia, and many other tissues
Demonstration of Muscarinic and Nicotinic Actions of
ACh, Dale’s Experiment
A.
B.
C.
D.
Two kinds of effects produced by ACh.
Ach causes a fall in BP due to arteriolar vasodilatation and slowing of the heart
A larger dose of ACh also produces bradycardia, further reducing BP
Atropine blocks the effect of ACh in lowering BP
Still under the influence of atropine, a much larger dose of ACh produces nicotinic
effects, causing a rise in BP and tachycardia due to stimulation of sympathetic
ganglia ( vasoconstriction) and secretion of adrenaline
Parasympathetic Nervous System,
Receptors for acetylcholine (cholinergic receptors)
I.
Nicotinic receptors, nAChRs (the nicotinic actions of ACh are those that can be
reproduced by the injection of nicotine) ---- Nicotinic receptors are ligand-gated
ion channels whose activation results in a rapid increase in cellular permeability
to sodium and calcium.
Location: nAChRs are located …..
1. At neuromuscular junctions of skeletal muscle (muscle type)





Postsynaptic
Excitatory (increases Na+ permeability)
Agonists: ACh, carbachol (CCh), suxamethonium
Stimulate skeletal muscle (contraction)
Antagonists: tubocurarine, hexamethonium
2. On postganglionic neurons in the autonomic ganglia (ganglion
type)





Postsynaptic
Excitatory (increases Na+ permeability)
Agonists: ACh, CCh, nicotine
Stimulate all autonomic ganglia
Antagonists: mecamylamine, trimetaphan
Parasympathetic Nervous System,
Cholinergic receptors
3. On some central nervous system neurons (CNS type)
 Pre- and postsynaptic
 Excitatory (increases Na+ permeability)
 Agonists: nicotine, ACh
 Pre- and postsynaptic stimulation of many brain regions
 Antagonists: mecamylamine, methylaconitine
4. On adrenal medulla
 ACh stimulates secretion of adrenaline from adrenal medulla
Parasympathetic Nervous System,
Cholinergic receptors
II. Muscarinic receptors, mAChRs (the muscarinic actions of ACh are those that can
be reproduced by the injection of muscarine) ---- Muscarinic receptors are GPCRs:
(odd-numbered members “M1, M3, M5) act through the inositol phosphate pathway,
while the even-numbered receptors (M2, M4) act by inhibting adenylate cyclase, and
thus reducing intracellular cAMP. mAChR also may activate or inhibit potassium
channels and calcium channels.
Location: mAChRs are located …
 in tissues innervated by postganglionic parasympathetic neurons such as
 On smooth muscle
 On cardiac muscle
 On gland cells
 See next table for details
 in postganglionic sympathetic neurons to sweat glands
 In the central nervous system
Main locations
Cellular
response
Functional
response
Agonists
Antagonists
P139
RDRM
2. G-protein-Coupled Receptors,
PIP2
Gq
Targets
PIP2:
phosphatidylinositol4,5-bisphosphate
IP3:
inositol-1,4,5trisphosphate
DAG:
1,2-diacylglycerol